All About CFTR

20/11/2011 09:52 OMIM Entry - *602421 - CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; CFTR
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602421
CYSTIC IIROSIS TRANSMIMRANI CONDUCTANCI
RIGULATOR, CITR
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ATI-INDING CASSITTI, SUIAMILY C, MIMIR 7, ACC7
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(from NCBI)
Gcnc Phcnntypc Rc!atinnships
TEXT
Dcscriptinn
Cyslic fibrosis lransmembrane conduclance reguIalor (CITR) funclions as a chIoride channeI
and conlroIs lhe reguIalion of olher lransorl alhvays. Mulalions in lhe CITR gene have
been found lo cause cyslic fibrosis (CI, 219700) and congenilaI biIaleraI aIasia of lhe vas
deferens (CAVD, 277180).
C!nning
Riordan el aI. (1989) isoIaled overIaing cDNA cIones from eilheIiaI ceII Iibraries vilh a
genomic DNA segmenl conlaining a orlion of lhe ulalive CI gene. Transcrils
aroximaleIy 6,500 nucIeolides in size vere deleclabIe in lhe lissues affecled in alienls vilh
CI. The redicled rolein consisls of 2 simiIar molifs, each vilh a domain having roerlies
Location Phenotype Phenotype
MIM number
7q31.2 CongenilaI biIaleraI absence of vas deferens 277180
Cyslic fibrosis 219700
Sveal chIoride eIevalion vilhoul CI
ronchieclasis vilh or vilhoul eIevaled sveal chIoride 1, modifier of 211400
Hyerlrysinemia, neonalaI
Iancrealilis, idioalhic 167800
consislenl vilh membrane-associalion, and a domain beIieved lo be invoIved in ATI binding.
In CI alienls, a deIeled henyIaIanine residue occurs al lhe cenler of lhe ulalive firsl
nucIeolide-binding foId (NI). The redicled rolein has 1,480 amino acids vilh a moIecuIar
mass of 168,138 Da. The characlerislics are remarkabIy simiIar lo lhose of lhe mammaIian
muIlidrug resislanl I-gIycorolein (171050), vhich aIso mas lo 7q, and lo a number of olher
membrane-associaled roleins. To avoid confusion vilh lhe reviousIy named CI anligen
(123885), Riordan el aI. (1989) referred lo lhe rolein as cyslic fibrosis lransmembrane
conduclance reguIalor (CITR).
Cyslic fibrosis reresenls lhe firsl genelic disorder eIucidaled slriclIy by lhe rocess of reverse
genelics (Ialer caIIed osilionaI cIoning), i.e., on lhe basis of ma Iocalion bul vilhoul lhe
avaiIabiIily of chromosomaI rearrangemenls or deIelions such as lhose lhal have grealIy
faciIilaled revious success in lhe cIoning of human disease genes in Duchenne muscuIar
dyslrohy (310200), relinobIasloma (180200), and chronic granuIomalous disease (306400), for
examIe. y use of a combinalion of chromosome vaIking and |uming, Rommens el aI.
(1989) succeeded in covering lhe CI region on 7q. The |uming lechnique vas arlicuIarIy
usefuI in byassing 'uncIonabIe' regions, vhich are eslimaled lo conslilule 5% of lhe human
genome. (Yeasl arlificiaI chromosome (YAC) veclors reresenl an aIlernalive slralegy.) The
idenlificalion of undermelhyIaled CG isIands vas 1 li-off, anolher vas screening of a cDNA
Iibrary conslrucled from cuIlured sveal gIand ceIIs of a non-CI individuaI. The CI gene
roved lo be aboul 250,000 b Iong, a surrising finding since lhe absence of aarenl
genomic rearrangemenls in CI chromosomes and lhe evidence of a Iimiled number of CI
mulalions redicled a smaII mulalionaI largel.
Green and OIson (1990) described a generaI slralegy for cIoning and maing Iarge regions of
human DNA vilh yeasl arlificiaI chromosomes (YACs). y anaIyzing 30 YAC cIones from lhe
region of chromosome 7 conlaining lhe CITR gene, a conlig ma sanning more lhan 1.5 Mb
vas assembIed. IndividuaI YACs as Iarge as 790 kb and conlaining lhe enlire CI gene vere
conslrucled in vivo by meiolic recombinalion in yeasl belveen airs of overIaing YACs.
Anand el aI. (1991) described lhe hysicaI maing of a 1.5-Mb region encomassing 2
genelic Ioci fIanking lhe CI Iocus and conlained vilhin a series of YAC cIones. The enlire
CITR gene vas incIuded vilhin 1 of lhese YACs, a 310-kb cIone aIso conlaining fIanking
sequence in bolh lhe 5-rime and 3-rime direclions from lhe gene.
Gcnc 5tructurc
Riordan el aI. (1989) idenlified 24 exons in lhe CITR gene.
Wilh lhe hoe of idenlifying conserved regions of bioIogic inleresl by sequence comarison,
IIIsvorlh el aI. (2000) soughl lo eslabIish lhe sequence of lhe chromosomaI segmenls
encomassing lhe human CITR and mouse Cflr genes. acleriaI cIone-based hysicaI mas of
lhe reIevanl human and mouse genomic regions vere conslrucled, and minimaIIy overIaing
sels of cIones vere seIecled and sequenced. AnaIyses of lhe resuIling dala rovided insighls
aboul lhe organizalion of lhe CITR/Cflr genes and olenliaI sequence eIemenls reguIaling
lheir exression.
Mapping
Riordan el aI. (1989) maed lhe CITR gene lo chromosome 7q. Ior addilionaI informalion on
lhe maing of lhe gene for cyslic fibrosis, see 219700.
The maing of lhe murine equivaIenl of lhe WNT2 and MIT (164860) genes lo mouse
chromosome 6 (Chan el aI., 1989) slrongIy indicaled lhal lhe mouse equivaIenl of lhe cyslic
fibrosis gene is aIso Iocaled on chromosome 6. y Soulhern anaIysis of mouse/Chinese hamsler
somalic ceII hybrid DNAs, KeIIey el aI. (1992) maed lhe Cflr gene lo chromosome 6. Using
reslriclion fragmenl Ienglh varianls (RILVs) in lhe sludy of inlersecific backcrosses, SiegeI el
aI. (1992) demonslraled lhal lhe Cflr gene in lhe mouse is cIose lo Mel and CoIa-2. Trezise el aI.
(1992) demonslraled lhal lhe Cflr Iocus is on ral chromosome 4. Sludy of olher Ioci suggesled
lhal an anceslraI mammaIian chromosome is reresenled by lhe resenl-day ral chromosome
4: 5 genes are synlenic on ral chromosome 4 and mouse chromosome 6 bul are divided
belveen human chromosomes 7 and 12. Anolher 5 genes lhal are synlenic on ral chromosome
4 and human chromosome 7 are divided belveen chromosomes 5 and 6 in lhe mouse.
Gcnc Functinn
In addilion lo funclioning as a chIoride channeI, CITR conlroIs lhe reguIalion of olher
lransorl alhvays. Ior examIe, alienls vilh CI and lhe homozygous CITR-deficienl
mouse have enhanced sodium ion absorlion, lhis enhanced sodium ion absorlion is
correcled by addilion of a viIdlye coy of CITR. CITR and oulvardIy reclifying chIoride
channeIs (ORCCs) are dislincl channeIs bul are Iinked funclionaIIy via an unknovn reguIalory
mechanism. Schvieberl el aI. (1995) resenled resuIls from vhoIe-ceII and singIe-channeI
alch-cIam recordings, shorl-circuil currenl recordings, and ATI-reIease assays of normaI,
CI, and viIdlye or mulanl CITR-lransfecled CI airvay cuIlured eilheIiaI ceIIs indicaling
lhal CITR reguIales ORCCs by lriggering lhe lransorl of lhe olenl agonisl, ATI, oul of lhe
ceII. The resuIls suggesled lhal CITR funclions lo reguIale olher chIoride ion secrelory
alhvays in addilion lo conducling chIoride ion ilseIf.
A quaIily conlroI syslem lhal raidIy degrades abnormaI membrane and secrelory rolein is
slringenlIy aIied lo lhe CITR rolein, aroximaleIy 75% of lhe viIdlye recursor and
100% of lhe deII508 varianl are raidIy degraded before exiling from lhe endoIasmic
relicuIum (IR). }ensen el aI. (1995) demonslraled lhal CITR and resumabIy olher inlrinsic
membrane roleins are subslrales for roleasomaI degradalion during lheir maluralion vilhin
lhe endoIasmic relicuIum. Chang el aI. (1999) shoved lhal exorl-incomelenl CITR roleins
disIay muIliIe arginine-framed lrielide sequences. Inaclivalion of 4 of lhese molifs by
reIacemenl of arginine residues al osilions R29, R516, R555, and R766 vilh Iysine residues
simuIlaneousIy caused mulanl deII508 CITR rolein lo escae IR quaIily conlroI and
funclion al lhe ceII surface. Chang el aI. (1999) suggesled lhal inlerference vilh recognilion of
lhese signaIs may be heIfuI in lhe managemenl of CI.
Younger el aI. (2006) idenlified an IR membrane-associaled ubiquilin Iigase comIex
conlaining lhe I3 RMA1 (RNI5, 602677), lhe I2 UC6I (UI2}1), and derIin-1 (DIRL1,
608813) lhal cooeraled vilh lhe cylosoIic HSC70 (HSIA8, 600816)/CHII (STU1, 607207) I3
comIex lo lriage CITR and deIII508. DerIin-1 relained CITR in lhe IR membrane and
inleracled vilh RMA1 and UC6I lo romole roleasomaI degradalion of CITR. RMA1 couId
recognize foIding defecls in deII508 coincidenl vilh lransIalion, vhereas CHII aeared lo
acl osllransIalionaIIy. A foIding defecl in deII508 delecled by RMA1 invoIved lhe inabiIily of
lhe second membrane-sanning domain of CITR lo roducliveIy inleracl vilh N-lerminaI
domains. Younger el aI. (2006) concIuded lhal lhe RMA1 and CHII I3 ubiquilin Iigases acl
sequenliaIIy in IR membrane and cylosoI lo monilor lhe foIding slalus of CITR and deII508.
Randak el aI. (1997) exressed NI2 of CITR as a soIubIe rolein fused lo maIlose-binding
rolein in I. coIi and found lhal il calaIyzed hydroIysis of ATI lo form ADI and Ii. The ADI
roducl inhibiled ATIase aclivily. NI2 aIso hydroIyzed GTI lo GDI and Ii. In lhe resence
of AMI, hovever, lhe ATIase reaclion vas suerseded by adenyIale kinase aclivily, resuIling
in formalion of 2 ADI moIecuIes from ATI and AMI. Randak el aI. (1997) idenlified a lyicaI
adenyIale kinase-Iike AMI-binding sile in NI2.
To delermine lhe slrucluraI basis for lhe ATIase aclivily of CITR, Ram|eesingh el aI. (1999)
sludied lhe effecl of mulalions in lhe WaIker A consensus molifs on ATI hydroIysis by lhe
urified, inlacl rolein. Mulalion of lhe Iysine residue in lhe WaIker A molif of eilher NI
inhibiled lhe ATIase aclivily of urified, inlacl CITR rolein by grealer lhan 50%, suggesling
lhal lhe 2 NIs funclion cooeraliveIy in calaIysis. SurrisingIy, lhe rale of channeI galing vas
significanlIy inhibiled onIy vhen lhe mulalion vas in lhe second NI, suggesling lhal ATIase
aclivily may nol be lighlIy couIed lo channeI galing.
Randak and WeIsh (2003) demonslraled lhal fuII-Ienglh CITR and lhe isoIaled nucIeolide-
binding domain-2 (ND2) had ATIase and adenyIale kinase aclivilies foIIoving exression in
HeLa ceIIs. The adenyIale kinase inhibilor A5A inhibiled CITR CI- currenls, and il inhibiled
channeI aclivily by binding an ATI sile and an AMI sile. Adding AMI svilched enzymalic
aclivily of lhe ND2 oIyelide from ATIase lo adenyIale kinase. ATI and AMI aeared
lo induce dimerizalion belveen ND1 and ND2, causing lhe channeI lo oen. Randak and
WeIsh (2003) hyolhesized lhal al hysioIogic AMI concenlralions, lhe redominanl reaclion
reguIaling channeI aclivily is IikeIy adenyIale kinase.
}iang and IngeIhardl (1998) revieved lhe ceIIuIar helerogeneily of CITR exression and
funclion in lhe Iung and lhe imorlanl imIicalions for gene lheray of cyslic fibrosis.
Cyslic fibrosis is characlerized by ersislenl Iseudomonas aeruginosa coIonizalion of lhe
conducling airvays Ieading lo lhe migralion of infIammalory ceIIs, incIuding
oIymorhonucIear Ieukocyles (IMNs), inlo lhe airvays of CI alienls. IMNs reIease a
olenl chemokinelic and chemoallraclanl, Ieukolriene , during an infIammalory resonse,
resuIling in lhe furlher migralion of infIammalory ceIIs. CromveII el aI. (1981) demonslraled
lhe exislence of Ieukolrienes in lhe sulum of CI alienls. The oxidalive melaboIiles of
arachidonic acid and lhe infIammalory ceII-derived roleases have been imIicaled in lhe
deslruclion and shedding of lhe airvay eilheIia observed in CI. ased on lhese observalions,
il has been roosed lhal anliinfIammalory drugs mighl be usefuI in CI lheray. The
nonsleroidaI anliinfIammalory drug (NSAID) iburofen inhibils 5-Iioxygenase and hence
Ieukolriene formalion, suggesling lhal iburofen may be usefuI in lhe lrealmenl of CI. Ils
ossibIe benefil in CI, vilh no aarenl adverse effecls, vas reorled by Konslan el aI. (1995).
Hovever, olher effecls of iburofen may counleracl lheraeulic slralegies designed lo increase
CITR exression and/or funclion in secrelory eilheIia. Devor and SchuIlz (1998) evaIualed
lhe acule effecls of iburofen and saIicyIic acid on cAMI-medialed CI- secrelion in bolh
coIonic and airvay eilheIia and found lhal al a harmacoIogicaIIy reIevanl concenlralion lhe
drugs inhibiled chIoride ion secrelion across lhese eilheIia and lhal lhis inhibilion vas due al
Ieasl in arl lo lhe bIocking of lhe CITR CI- channeIs.
Wei el aI. (1998) sludied CITR channeI aclivily of malure R-domain mulanls vilh oinl
mulalions al siles olher lhan lhe redicled hoshoryIalion siles. WhoIe-ceII chIoride
conduclion vas increased in Xenous oocyles in|ecled vilh H620Q-CITR mRNA, bul
decreased in lhe I822K and I826K mulanls comared lo viIdlye CITR. Anion ermeabiIily
and singIe-channeI conduclances did nol differ from viIdlye for any of lhe mulanls. CeII-
allached singIe channeI sludies in COS ceIIs reveaIed lhal bolh oen channeI robabiIily
and/or lhe number of funclionaI channeIs vere eilher higher (H260Q) or Iover (I822K and
I826K) lhan in viIdlye CITR. These resuIls suggesled lhal siles olher lhan lhe
hoshoryIalion siles in lhe R-domain infIuence galing.
Chanson el aI. (1999) comared ga |unclionaI couIing in a human ancrealic ceII Iine
harboring lhe deII508 mulalion in CITR and in lhe same ceII Iine in vhich lhe defecl vas
correcled by lransfeclion vilh viIdlye CITR. Ixosure lo agenls lhal eIevale inlraceIIuIar
cAMI or secificaIIy aclivale rolein kinase A evoked chIoride ion currenls and markedIy
increased |unclionaI conduclance of CITR-exressing ceII airs, bul nol in lhe arenlaI ceIIs.
Thus, lhe exression of funclionaI CITR reslored lhe cAMI-deendenl reguIalion of
|unclionaI conduclance as veII as lhe chIoride ion channeI in CI ceIIs. ConsequenlIy, defeclive
reguIalion of ga |unclion channeIs may conlribule lo lhe aIlered funclions of lissues affecled
in CI.
Reddy el aI. (1999) demonslraled lhal in freshIy isoIaled normaI sveal ducls, eilheIiaI sodium
channeI (INaC, see 600228) aclivily is deendenl on, and increases vilh, CITR aclivily. Reddy
el aI. (1999) aIso found lhal lhe rimary defecl in chIoride ermeabiIily in cyslic fibrosis is
accomanied secondariIy by a sodium conduclance in lhis lissue lhal cannol be aclivaled.
Thus, reduced saIl absorlion in cyslic fibrosis is due nol onIy lo oor chIoride conduclance
bul aIso lo oor sodium conduclance.
WeixeI and radbury (2000) used in vivo cross-Iinking and in vilro uII-dovn assays lo shov
lhal fuII-Ienglh CITR binds lo lhe endocylic adalor comIex AI2 (see 601024). Subslilulion of
an aIanine residue for lyrosine al osilion 1424 significanlIy reduced lhe abiIily of AI2 lo bind
lhe C lerminus of CITR. Hovever, mulalion lo a henyIaIanine residue, vhich is normaIIy
found in dogfish CITR al lhis osilion, did nol erlurb AI2 binding. Taken logelher, lhese
dala suggesl lhal lhe C lerminus of CITR conlains a lyrosine-based inlernaIizalion signaI lhal
inleracls vilh lhe endocylic adalor comIex AI2 lo faciIilale efficienl enlry of CITR inlo
cIalhrin-coaled vesicIes.
Wang el aI. (2000) idenlified a hydrohiIic CITR-binding rolein, CAI70, vhich is
concenlraled on lhe aicaI surfaces. CAI70 had reviousIy been idenlified by Kocher el aI.
(1998) as IDZK1 (603831). The rolein conlains 4 IDZ domains, 3 of vhich are caabIe of
binding lo lhe CITR C lerminus. Linking al Ieasl 2 CITR moIecuIes via cyloIasmic C-
lerminaI binding by eilher muIlivaIenl CAI70 or a bivaIenl monocIonaI anlibody olenliales
lhe CITR chIoride channeI aclivily. Thus, lhe CITR channeI can be svilched lo a more aclive
conducling slale via a modificalion of inlermoIecuIar CITR-CITR conlacl lhal is enhanced by
an accessory rolein.
Moyer el aI. (2000) reorled lhal lhe C lerminus of CITR conslilules a IDZ-inleracling domain
lhal is required for CITR oIarizalion lo lhe aicaI Iasma membrane and inleraclion vilh lhe
IDZ domain-conlaining rolein II50 (604990). IDZ-inleracling domains are lyicaIIy
comosed of lhe C-lerminaI 3 lo 5 amino acids, vhich in CITR are gIn-as-lhr-arg-Ieu. Ioinl
subslilulion of lhe Ieucine al osilion 0 vilh aIanine abrogaled aicaI oIarizalion of CITR,
inleraclion belveen CITR and II50, efficienl exression of CITR in lhe aicaI membrane,
and chIoride secrelion. Ioinl subslilulion of lhe lhreonine al osilion -2 vilh aIanine or vaIine
had no effecl on lhe aicaI oIarizalion of CITR, bul reduced inleraclion belveen CITR and
II50, efficienl exression of CITR in lhe aicaI membrane, and chIoride secrelion. y
conlrasl, individuaI oinl subslilulion of any of lhe olher amino acids in lhe IDZ domain had
no effecl on measured aramelers. Moyer el aI. (2000) concIuded lhal mulalions lhal deIele lhe
C lerminus of CITR may cause cyslic fibrosis because CITR is nol oIarized, comIexed vilh
II50, or efficienlIy exressed in lhe aicaI membrane of eilheIiaI ceIIs.
CITR reguIales olher lransorlers, incIuding chIoride-couIed bicarbonale lransorl. AIkaIine
fIuids are secreled by normaI lissues, vhereas acidic fIuids are secreled by mulanl CITR-
exressing lissues, indicaling lhe imorlance of lhis aclivily. icarbonale and H affecl mucin
viscosily and bacleriaI binding. Choi el aI. (2001) examined chIoride-couIed bicarbonale
lransorl by CITR mulanls lhal relain subslanliaI or normaI chIoride channeI aclivily. Choi el
aI. (2001) demonslraled lhal mulanls reorled lo be associaled vilh cyslic fibrosis vilh
ancrealic insufficiency do nol suorl bicarbonale lransorl, and lhose associaled vilh
ancrealic sufficiency shov reduced bicarbonale lransorl. Choi el aI. (2001) concIuded lhal
lheir findings demonslrale lhe imorlance of bicarbonale lransorl in lhe funclion of secrelory
eilheIia and in CI.
Rovnlree el aI. (2001) shoved lhal removaI of a DNase I hyersensilive sile (DHS) in inlron 1
(185+10 kb) of CITR aboIished lhe aclivily of lhis DHS in lransienl lransfeclion assays of
reorler/enhancer gene conslrucls. SlabIe lransfeclions of a human coIon carcinoma ceII Iine
vilh CITR-conlaining YACs shoved lhal lranscrilion from lhe DHS eIemenl-deIeled YAC
vas reduced by 60% comared lo lhe inlacl conslrucl. In lransgenic mice, deIelion of lhe
inlron 1 DHS had no effecl on exression in lhe Iung, bul reduced exression in lhe inlesline
by 60%. The aulhors concIuded lhal lhe reguIalory eIemenl associaled vilh lhe inlron 1 DHS is
lissue-secific and is required for normaI CITR exression IeveIs in lhe inleslinaI eilheIium
in vivo.
CaIIen el aI. (2000) deveIoed a cAMI-medialed sveal rale lesl lhal aIIovs lhe quanlilalive
discriminalion of CITR funclion, lhereby indicaling CI genolye: CI, CI carrier, and non-CI.
CaIIen el aI. (2000) remarked lhal lhis lesl may be heIfuI in lhe diagnosis of ambiguous cases
and in sludies of nev agenls lo increase lhe funclion of CITR.
In CITR, an abbrevialed oIyyrimidine lracl belveen lhe branch oinl A and lhe 3-rime
sIice sile is associaled vilh increased exon skiing and disease. Hovever, many exons, bolh
in CITR and in olher genes, have shorl oIyyrimidine lracls in lheir 3-rime sIice siles, yel
lhey are nol skied. Hefferon el aI. (2002) examined lhe moIecuIar basis of lhe skiing of
conslilulive exons in mRNAs and lhe skiing of exon 9 in lhe CITR gene. They reorled
observalions in human, mouse, and shee lhal Iaced reneved emhasis on devialions al 3-
rime sIice siles in nucIeolides olher lhan lhe invarianl GT, arlicuIarIy vhen such changes
are found in con|unclion vilh olher aIlered sIicing sequences, such as a shorlened
oIyyrimidine lracl. Hefferon el aI. (2002) suggesled lhal carefuI inseclion of enlire 5-rime
sIice siles may idenlify conslilulive exons lhal are vuInerabIe lo skiing.
Using a quanlilalive mRNA assay al 14 lime oinls lhrough ovine geslalion, roackes-Carler
el aI. (2002) delermined lhal CITR exression vas highesl al lhe slarl of lhe second lrimesler
foIIoved by a graduaI decIine lhrough lo lerm. In conlrasl, eilheIiaI sodium channeI
(SCNN1A, 600228) exression increased from lhe slarl of lhe lhird lrimesler. The aulhors
roosed a roIe for CITR in differenlialion of lhe resiralory eilheIium and suggesled lhal ils
exression IeveIs are nol mereIy refIecling ma|or changes in lhe sodium/chIoride buIk fIov
cIose lo lerm.
IideIman el aI. (2002) found lhal NI1 of CITR inleracled seIecliveIy vilh hoshalidyIserine
ralher lhan hoshalidyIchoIine. In conlrasl, NI1 vilh lhe deIla-I508 mulalion Iosl lhe
abiIily lo discriminale belveen lhese hoshoIiids. In mouse L ceIIs exressing deIla-I508
CITR, reIacemenl of hoshalidyIchoIine by noncharged anaIogs Ied lo increased CITR
rolein exression, suggesling lhal aberranl inleraclion belveen lhe deIla-I508 NI1 domain
and hoshoIiid chaerones may conlribule lo lhe rocessing defecl of lhe deIla-I508 CITR
mulanl.
IIasma membrane exression of deIla-I508 CITR can be rescued in eilheIiaI ceIIs by
cuIluring lhem al 27 degrees CeIsius for 24 hours. y screening 100,000 diverse smaII
moIecuIes, Yang el aI. (2003) found lhal lelrahydrobenzolhiohenes couId aclivale coId-
induced membrane-associaled deIla-I508 CITR, resuIling in reversibIe CI- conduclance in
lransfecled ral lhyroid eilheIiaI ceIIs. SingIe-ceII voIlage cIam anaIysis shoved characlerislic
CITR currenls. Aclivalion required Iov concenlralions of a cAMI agonisl, mimicking lhe
normaI hysioIogic resonse.
Reddy and Quinlon (2003) reorled hoshoryIalion- and ATI-indeendenl aclivalion of
CITR by cyloIasmic gIulamale lhal excIusiveIy eIicils chIoride bul nol bicarbonale
conduclance in lhe human sveal ducl. They aIso shoved lhal lhe anion seIeclivily of
gIulamale-aclivaled CITR is nol inlrinsicaIIy fixed, bul can undergo a dynamic shifl lo
conducl bicarbonale by a rocess invoIving ATI hydroIysis. Ducl ceIIs from alienls vilh lhe
deIla-I508 CITR mulalion (602421.0001) shoved no gIulamale/ATI-aclivaled chIoride or
bicarbonale conduclance. In conlrasl, ducl ceIIs from helerozygous alienls vilh R117H
(602421.0005)/deIla-I508 mulalions aIso Iosl mosl of lhe chIoride conduclance, yel relained
significanl bicarbonale conduclance. Reddy and Quinlon (2003) concIuded lhal nol onIy does
gIulamale conlroI neuronaI ion channeIs, bul il can aIso reguIale anion conduclance and
seIeclivily of CITR in nalive eilheIiaI ceIIs. They roosed lhal lhe Ioss of lhis uniqueIy
reguIaled bicarbonale conduclance is mosl IikeIy resonsibIe for lhe more severe forms of
cyslic fibrosis alhoIogy.
Wang el aI. (2003) demonslraled lhal endomelriaI eilheIiaI ceIIs ossess a CITR-medialed
bicarbonale lransorl mechanism. CocuIlure of serm vilh endomelriaI ceIIs lrealed vilh
anlisense oIigonucIeolide againsl CITR, or vilh bicarbonale secrelion-defeclive CI eilheIiaI
ceIIs, resuIled in Iover serm caacilalion and egg-ferliIizing abiIily. These resuIls vere
considered consislenl vilh a crilicaI roIe of CITR in conlroIIing ulerine bicarbonale secrelion
and lhe ferliIizing caacily of serm, roviding a Iink belveen defeclive CITR and Iover
femaIe ferliIily in CI.
Shee and human CITR genes shov a graduaI decIine in exression during Iung
deveIomenl, from lhe earIy midlrimesler lhrough lo lerm. MoucheI el aI. (2003) idenlified a
noveI 5-rime exon of lhe shee CITR gene (ov1a) lhal occurs in 2 sIice forms (ov1aL and
ov1aS), vhich are bolh muluaIIy excIusive vilh exon 1. CITR lranscrils, incIuding ov1aL and
ov1aS, vere resenl al Iov IeveIs in many shee lissues, hovever, ov1aS shoved lemoraI
and saliaI reguIalion during felaI Iung deveIomenl, being mosl abundanl vhen CITR
exression slarls lo decIine. AIlernalive 5-rime exons -1a and 1a in lhe human CITR gene
aIso shoved changes in exression IeveIs lhrough Iung deveIomenl. SlrucluraI evaIualion of
ov1aL and ov1aS reveaIed lhe olenliaI lo form exlremeIy slabIe secondary slruclures vhich
vouId cause ribosomaI subunil delachmenl. Iurlher, lhe Ioss of exon 1 from lhe CITR
lranscril removed molifs lhal are lhoughl cruciaI for normaI lrafficking of lhe CITR rolein.
MoucheI el aI. (2003) hyolhesized lhal recruilmenl of lhese aIlernalive uslream exons may
reresenl a noveI mechanism of deveIomenlaI reguIalion of CITR exression.
Iischer el aI. (2004) found lhal vilamin C induced lhe oening of CITR chIoride channeIs by
increasing lhe average oen robabiIily in lhe absence of deleclabIe increased cAMI IeveIs.
Ixosure of lhe aicaI airvay surface lo hysioIogic concenlralions of vilamin C slimuIaled
lranseilheIiaI chIoride secrelion. When insliIIed inlo lhe nasaI eilheIium of human sub|ecls,
vilamin C aclivaled chIoride lransorl. Iischer el aI. (2004) concIuded lhal ceIIuIar vilamin C,
via ils aicaI vilamin C lransorler, is a bioIogic reguIalor of CITR-medialed chIoride
secrelion in eilheIia.
Vergani el aI. (2005) used singIe-channeI recording melhods on inlacl CITR moIecuIes lo
direclIy foIIov oening and cIosing of lhe channeI gales, and reIaled lhese occurrences lo
ATI-medialed evenls in lhe nucIeolide binding domains (NDs). They found lhal energelic
couIing belveen 2 CITR residues, execled lo Iie on oosile sides of ils redicled ND1-
ND2 dimer inlerface, changes in concerl vilh channeI galing slalus. The 2 monilored side
chains are indeendenl of each olher in cIosed channeIs bul become couIed as lhe channeIs
oen. Vergani el aI. (2005) concIuded lhal lheir resuIls direclIy Iink ATI-driven lighl
dimerizalion of CITR's cyloIasmic nucIeolide binding domains lo oening of lhe ion channeI
in lhe lransmembrane domains. This eslabIishes a moIecuIar mechanism, invoIving dynamic
reslrucluring of lhe ND dimer inlerface, lhal is robabIy common lo aII members of lhe AC
rolein suerfamiIy.
Using roleomics lo assess gIobaI CITR rolein inleraclions, Wang el aI. (2006) shoved lhal
HSI90 (see 140571) cochaerones moduIaled HSI90-deendenl slabiIily of CITR rolein
foIding in lhe IR. SmaII inlerfering RNA-medialed arliaI siIencing of lhe HSI90 cochaerone
ATIase reguIalor AHA1 (AHSA1, 608466) in human embryonic kidney and Iung ceII Iines
rescued deIivery of CITR deIla-I508 lo lhe ceII surface. Wang el aI. (2006) roosed lhal
faiIure of CITR deIla-I508 lo achieve an energelicaIIy favorabIe foId in resonse lo sleady-
slale dynamics of lhe chaerone foIding environmenl is resonsibIe for lhe alhohysioIogy
of CI.
Using roleomic aroaches, TheIin el aI. (2007) shoved lhal fiIamin (ILNA, 300017)
associales vilh lhe exlreme CITR N lerminus, and found lhal lhe disease-causing S13I
mulalion disruls lhis inleraclion. CeII sludies reveaIed lhal ILNA lelhers Iasma membrane
CITR lo lhe underIying aclin nelvork, slabiIizing CITR al lhe ceII surface and reguIaling lhe
Iasma membrane dynamics and confinemenl of lhe channeI. In lhe absence of fiIamin
binding, CITR is raidIy inlernaIized from lhe ceII surface, vhere il accumuIales remalureIy
in Iysosomes and is uIlimaleIy degraded. TheIin el aI. (2007) concIuded lhal lhe CITR N
lerminus Iays a roIe in lhe reguIalion of lhe Iasma membrane slabiIily and melaboIic
slabiIily of CITR, and slaled lhal S13I is lhe firsl missense mulalion in CITR found lo disrul
a rolein-rolein inleraclion.
Binchcmica! Fcaturcs
Serohi|os el aI. (2008) resenled a 3-dimensionaI slruclure of CITR, conslrucled by moIecuIar
modeIing and suorled biochemicaIIy, in vhich he508 mediales a lerliary inleraclion
belveen lhe surface of lhe N-lerminaI nucIeolide-binding domain and cyloIasmic Ioo-4 in
lhe C-lerminaI membrane-sanning domain. This cruciaI cyloIasmic membrane inlerface is
invoIved in reguIalion of channeI galing and exIains lhe sensilivily of CITR assembIy lo
disease-associaled mulalions in cyloIasmic Ioo-4, as veII as in lhe N-lerminaI nucIeolide-
binding domain.
Mn!ccu!ar Gcnctics
Kerem el aI. (1989) found lhal aroximaleIy 70% of lhe mulalions in CI alienls corresond
lo a secific deIelion of 3 baseairs, vhich resuIls in lhe Ioss of a henyIaIanine residue al
amino acid osilion 508 of lhe ulalive roducl of lhe CI gene. HaIolye dala based on DNA
markers cIoseIy Iinked lo lhe ulalive disease gene Iocus suggesled lhal lhe remainder of lhe
CI mulanl gene ooI consisls of muIliIe, differenl mulalions. A smaII sel of lhese Ialler
mulanl aIIeIes (aboul 8%) may confer residuaI ancrealic exocrine funclion in a subgrou of
alienls vho are ancrealic sufficienl. The discovery lhal lhe mosl common CI abnormaIily
gives rise lo lhe Ioss of a singIe amino acid residue in a funclionaI domain suggesls lhal lhe
henolye of CI is nol due lo comIele Ioss of funclion of lhe gene roducl. The silualion may
be comarabIe lo lhal in sickIing disorders, in vhich a secific subsel of mulalions in lhe bela-
gIobin gene gives rise lo an aIlered rolein vilh unusuaI behavior. ComIele absence of
funclion of lhe bela-gIobin gene gives rise lo a differenl henolye, nameIy, bela-0-
lhaIassemia, simiIarIy, homozygous Ioss of funclion of lhe CI gene may Iead lo a dislinclive
henolye.
TraneII el aI. (1991) sludied CITR mRNA lranscrils in resiralory lracl eilheIiaI ceIIs
recovered by fiberolic bronchoscoy vilh a cyloIogy brush. They found lhal lhe lranscrils
refIecled lhe normaI and lhe deIla-I508 aIIeIes in aroriale roorlions. CITR mRNA
lranscrils vere exressed in nasaI, lracheaI, and bronchiaI eilheIiaI ceIIs in aboul 1 lo 2
coies er ceII, more lhan 100-foId grealer lhan in haryngeaI eilheIium. ZeilIin el aI. (1992)
idenlified a oIycIonaI anlibody lhal vas used lo delecl lhe CITR gIycorolein in biosied
human nasaI and bronchiaI lissues and in lhe aicaI membrane fraclion of iIeaI viIIus lissue.
LeveIs of lhe rolein vere moduIaled harmacoIogicaIIy.
ZieIenski el aI. (1991) found a cIusler of highIy oIymorhic dinucIeolide reeals in inlron 17b
of lhe CITR gene, 200 b dovnslream from lhe receding exon. Al Ieasl 24 aIIeIes, vilh sizes
ranging from 7 lo 56 unils of a TA reeal, vere idenlified in a aneI of 92 unreIaled carriers of
CI. The common aIIeIes had 7, 30, and 31 dinucIeolide unils, vilh frequencies of 0.22, 0.19, and
0.12, resecliveIy, among lhe non-CI chromosomes. A Iess oIymorhic dinucIeolide cIusler, a
CA reeal, vas aIso delecled in a region 167 b dovnslream from lhe TA reeal. This varied
from 11 lo 17 dinucIeolide unils and aeared lo bear an inverse reIalionshi lo lhal of lhe TA
reeals. These reeals vere considered lo be usefuI in genelic Iinkage sludies, in counseIing
CI famiIies vilh unknovn mulalions, and in lracing lhe origins of various mulanl CI aIIeIes.
MorraI el aI. (1991) and Chehab el aI. (1991) aIso described reeals vilhin inlrons of lhe CITR
gene. The significance of lhe inverse correIalion belveen lhe Ienglhs of lhe 2 reeal regions
vas nol invesligaled, Ienglh comensalion may be invoIved and may have funclionaI
imorlance.
ChaIkIey and Harris (1991) made use of 'ecloic' or 'iIIegilimale' lranscrilion of CI mRNA in
Ieukocyles in lhe deleclion of CI mulalions. y use of ICR, il vas ossibIe lo delecl such
ecloic lranscrilion as in lhe case of olher genes such as lhose for dyslrohin (300377) and
faclor VIII (300841). Ionknechlen el aI. (1992) exlended lhese observalions, using lhe ICR
reaclion for delecling CITR mulalions in lhe sludy of Iymhocyles and IymhobIasls. Ierrie el
aI. (1992) aIied lhe amIificalion refraclory mulalion syslem (ARMS) lo lhe deleclion of
mulalions in lhe CITR gene.
Culling el aI. (1990) soughl mulalions in lhe 2 NIs of CITR by nucIeolide sequencing of
exons 9, 10, 11, and 12 (encoding lhe firsl NI) and exons 20, 21, and 22 (encoding mosl of lhe
second NI) from 20 Caucasian and 18 American bIack CI alienls. They found a cIusler of 4
mulalions in a 30-b region of exon 11. Three of lhe mulalions caused amino acid subslilulions
al residues lhal are highIy conserved among lhe CITR rolein, lhe muIliIe-drug-resislance
roleins, and ATI-binding membrane-associaled lransorl roleins. The fourlh mulalion
crealed a remalure lerminalion signaI.
To exIore lhe moIecuIar mechanisms resonsibIe for defeclive chIoride lransorl in alienls
vilh CI, Yang el aI. (1993) sludied lhe rocessing, IocaIizalion, and funclion of viIdlye,
deII508 (602421.0001) and G551D (602421.0013) CITR in relrovirus lransduced L ceIIs. They
concIuded lhal lhe moIecuIar alhoIogy of G551D is exIained by an abnormaIily in channeI
aclivily, vhiIe lhe defecl in deII508 is a combinalion of misIocaIizalion and inslabiIily of lhe
rolein in addilion lo arliaI defecls in channeI funclion. Some of lheir observalions suggesled
lhe ossibiIily of harmacoIogic lheraies for CI based on aclivaling Ialenl CITR.
Nol onIy is lhere helerogeneily in lhe mulalions causing cyslic fibrosis, bul lhe alhogenelic
mechanisms aIso vary. DeIelion of henyIaIanine-508 aears lo cause disease by abrogaling
normaI biosynlhelic rocessing and lhereby resuIling in relenlion and degradalion of lhe
mulanl rolein vilhin lhe endoIasmic relicuIum. Olher mulalions, such as lhe reIaliveIy
common gIy551-lo-as mulalion, aear lo be normaIIy rocessed and, lherefore, musl cause
disease lhrough some olher mechanism. ecause bolh deIla-I508 and G551D occur vilhin a
redicled nucIeolide-binding domain (ND) of CITR, Logan el aI. (1994) lesled lhe infIuence
of lhese mulalions on nucIeolide binding by lhe rolein. They found lhal G551D and lhe
corresonding mulalion in lhe CITR second nucIeolide binding domain, gIy1349-lo-as
(G1349D), Ied lo decreased nucIeolide binding by CITR NDs, vhiIe lhe deIla-I508 mulalion
did nol aIler nucIeolide binding. These resuIls imIicaled defeclive ATI-binding as lhe
alhogenic mechanism of a reIaliveIy common mulalion Ieading lo CI and suggesled lhal
slrucluraI inlegrily of a highIy conserved region resenl in over 30 rokaryolic and eukaryolic
nucIeolide-binding domains may be crilicaI for normaI nucIeolide binding.
CITR vas one of lhe genes used by MarshaI el aI. (1995) lo lesl lheir melhod of mulalion
deleclion using bacleriohage resoIvases, vhose funclion in vivo is lo cIeave branched DNA
and vhich have lhe roerly of recognizing mismalched bases in doubIe-slranded DNA and
culling lhe DNA al lhe mismalch. The nev melhod, lermed enzyme mismalch cIeavage (IMC)
by YouiI el aI. (1995), vho indeendenlIy deveIoed lhe melhod, lakes advanlage of lhis
characlerislic of resoIvases lo delecl individuaIs vho are helerozygous al a given sile.
RadioIabeIed DNA is cIeaved by lhe resoIvase al lhe sile of mismalch in heleroduIex DNA
and digeslion is monilored on a geI. Thus, bolh lhe resence and lhe eslimaled osilion of an
aIleralion is reveaIed. One may lhink of lhe resoIvase as a reslriclion enzyme lhal onIy
recognizes mulalions.
There is a oIymorhic slring of lhymidines al lhe end of inlron 8 of lhe CITR gene, 3
differenl aIIeIes can be found deending on lhe number of lhymidines (5, 7, or 9) resenl al
lhis sile (Chu el aI., 1991). The number of lhymidines delermines lhe efficiency by vhich lhe
inlron 8 sIice accelor sile is used. The efficiency decreases vhen a shorler slrelch of
lhymidine residues is found. A higher roorlion of CITR lranscrils lhal Iack exon 9
sequences, vhich encode arl of lhe funclionaIIy imorlanl firsl nucIeolide-binding domain,
viII lherefore be found vhen a shorler slrelch of lhymidine residues is resenl (Chu el aI.,
1993). If a CITR gene vilh lhe arg117-lo-his (R117H) mulalion (602421.0005) harbors a T5
aIIeIe, lhe mulanl gene viII be resonsibIe for CI. An R117H mulanl CITR gene lhal harbors a
T7 aIIeIe can eilher resuIl in CI or CAVD (Kieseveller el aI., 1993). Teng el aI. (1997) noled
lhal lhe T5 aIIeIe resuIls in lhe mosl inefficienl use of lhis sIice accelor sile. Mosl CITR
lranscrils from a T5 aIIeIe viII lherefore Iack exon 9 sequencing. Such exon 9-deficienl CITR
lranscrils are knovn lo be lransIaled inlo CITR roleins lhal viII nol malure, and viII
lherefore nol funclion as chIoride channeIs in lhe aicaI membrane of eilheIiaI ceIIs. Among
CAVD alienls, lhe frequency of lhis T5 aIIeIe is 4- lo 6-foId higher lhan in lhe conlroI
ouIalion (see 602421.0005). Teng el aI. (1997) anaIyzed CITR lranscrils quaIilaliveIy and
quanlilaliveIy in nasaI eilheIiaI and vas deferens ceIIs. AIlernalive sIicing of exon 9, vhich
had been knovn lo occur in nasaI eilheIiaI ceIIs, aIso occurred in vas deferens ceIIs. The
exlenl of lhis aIlernalive sIicing vas delermined by lhe aIIeIe resenl al lhe Tn Iocus al lhe
end of inlron 8 of lhe CITR gene. Hovever, lhe roorlion of lranscrils Iacking exon 9
sequences vas increased in vas deferens ceIIs comared vilh nasaI eilheIiaI ceIIs,
indeendenl of lhe Tn genolye. Thus, Teng el aI. (1997) osluIaled lhal lissue-secific
differences in lhe roorlion of CITR lranscrils Iacking exon 9 sequences may conlribule lo
lhe lissue-secific disease henolye observed in individuaIs vilh CAVD.
esides lhe oIymorhic Tn Iocus, more lhan 120 oIymorhisms have been described in lhe
CITR gene. Cuens el aI. (1998) hyolhesized lhal lhe combinalion of arlicuIar aIIeIes al
severaI oIymorhic Ioci mighl resuIl in Iess funclionaI or even insufficienl CITR rolein.
AnaIysis of 3 oIymorhic Ioci vilh frequenl aIIeIes in lhe generaI ouIalion shoved lhal, in
addilion lo lhe knovn effecl of lhe Tn Iocus, lhe quanlily and quaIily of CITR lranscrils
and/or roleins vere affecled by 2 olher oIymorhic Ioci: M470V (602421.0023) and a
dinucIeolide reeal oIymorhism (TG)m. On a T7 background, lhe (TG)11 aIIeIe gave a 2.8-
foId increase in lhe roorlion of CITR lranscrils lhal Iacked exon 9, and (TG)12 gave a 6-
foId increase, comared vilh lhe (TG)10 aIIeIe. T5 CITR genes derived from alienls vere
found lo carry a high number of TG reeals, vhiIe T5 CITR genes derived from heaIlhy CI
falhers harbored a Iov number of TG reeals. Moreover, il vas found lhal M470 CITR
roleins malured more sIovIy, and lhal lhey had a 1.7-foId increased inlrinsic chIoride
channeI aclivily comared vilh V470 CITR roleins, suggesling lhal lhe M470V Iocus mighl
aIso Iay a roIe in lhe arliaI enelrance of T5 as a disease mulalion. Such oIyvaIenl mulanl
genes couId exIain vhy aarenlIy normaI CITR genes cause disease. Moreover, lhey mighl
be resonsibIe for varialion in lhe henolyic exression of CITR mulalions. This sludy
suggesled lhal genelic and funclionaI sludies of oIymorhisms in reIalion lo genelic diseases
viII become of ma|or inleresl, in reIalion bolh lo monogenic disorders and comIex lrails.
In 9 of 16 cases of disseminaled bronchieclasis (56%), Iignalli el aI. (1996) found lhe 5T aIIeIe
in inlron 8 (IVS8-5T) and/or a CITR gene mulalion. The resuIls confirmed, al lhe moIecuIar
genelic IeveI, a cIinicaI conneclion belveen CI and one obslruclive uImonary disease,
disseminaled bronchieclasis of unknovn origin. SimiIarIy, Girodon el aI. (1997) sludied 32
alienls vilh disseminaled bronchieclasis and a cIinicaIIy isoIaled resiralory syndrome.
AnaIysis of aII CITR gene exons and lheir fIanking regions demonslraled 13 CITR gene
mulalions in 16 differenl aIIeIes. Six of lhese mulalions, vhich had reviousIy been reorled
as CI defecls, vere found in 9 aIIeIes. Iour alienls vere comound helerozygoles, 6 vere
helerozygous for a mulalion. Girodon el aI. (1997) concIuded lhal CITR gene mulalions may
Iay a roIe in bronchieclalic Iung disease, ossibIy in a muIlifacloriaI conlexl.
Il has been roosed lhal in helerozygous slale mulalions of lhe CITR gene rovide increased
resislance lo infeclious diseases, lhereby mainlaining mulanl CITR aIIeIes al high IeveIs in
seIecled ouIalions. Iier el aI. (1998) invesligaled vhelher lyhoid fever couId be one such
disease. This disease is inilialed vhen SaImoneIIa lyhi enlers gaslroinleslinaI eilheIiaI ceIIs
for submucosaI lransIocalion. They found lhal S. lyhi, bul nol lhe reIaled murine alhogen S.
lyhimurium, uses CITR for enlry inlo eilheIiaI ceIIs. CeIIs exressing viIdlye CITR
inlernaIized more S. lyhi lhan isogenic ceIIs exressing lhe mosl common CITR mulalion,
deIla-I508 (602421.0001). MonocIonaI anlibodies and synlhelic elides conlaining a sequence
corresonding lo lhe firsl redicled exlraceIIuIar domain of CITR inhibiled ulake of S. lyhi.
Helerozygous deIla-I508 Cflr mice lransIocaled 86% fever S. lyhi inlo lhe gaslroinleslinaI
submucosa lhan did viIdlye Cflr mice, no lransIocalion occurred in deIla-I508 Cflr
homozygous mice. The Cflr genolye had no effecl on lhe lransIocalion of S. lyhimurium.
ImmunoeIeclron microscoy reveaIed lhal more CITR bound S. lyhi in lhe submucosa of
Cflr viIdlye mice lhan in deIla-I508 helerozygous mice. Iier el aI. (1998) concIuded lhal
diminished IeveIs of CITR in helerozygoles decreases suscelibiIily lo lyhoid fever.
Van de Vosse el aI. (2005) lesled lhe hyolhesis lhal CITR helerozygoles have a seIeclive
advanlage againsl lyhoid, vhich may be conferred lhrough reduced allachmenl of S. lyhi lo
lhe inleslinaI mucosa. They genolyed alienls and conlroIs in a lyhoid endemic area in
Indonesia for 2 highIy oIymorhic markers in CITR and lhe mosl common CI mulalion,
I508deI. Consislenl vilh lhe aarenlIy very Iov incidence of CI in Indonesia, lhe I508deI
mulalion vas nol resenl in any alienls or conlroIs. Hovever, lhey found significanl
associalion belveen a common oIymorhism in inlron 8 (16 or 17 CA reeals) and seIeclive
advanlage againsl lyhoid.
Sharer el aI. (1998) sludied 134 conseculive alienls vilh chronic ancrealilis (167800)
(aIcohoI-reIaled disease in 71, hyeraralhyroidism in 2, hyerlrigIyceridemia in 1, and
idioalhic disease in 60). DNA vas examined for 22 mulalions of lhe CITR gene lhal logelher
accounl for 95% of aII mulalions in alienls vilh cyslic fibrosis in lhe norlhvesl of IngIand
vhere lhe sludy vas erformed. They aIso delermined lhe Ienglh of lhe noncoding sequence
of lhymidines in inlron 8, since lhe shorler lhe sequence, lhe Iover lhe roorlion of normaI
CITR mRNA. None of lhe alienls had a mulalion on bolh coies of lhe CITR gene. Iighleen
alienls (13.4%), incIuding 12 vilhoul aIcohoIism, had a CITR mulalion on 1 chromosome, as
comared vilh a frequency of 5.3% among 600 IocaI unreIaled arlners of ersons vilh a
famiIy hislory of cyslic fibrosis (I Iess lhan 0.001). A lolaI of 10.4% of lhe alienls had lhe 5T
aIIeIe in inlron 8 (14 of 134), vhich is lvice lhe execled frequency (I 0.008). Iour alienls
vere helerozygous for bolh a CITR mulalion and lhe 5T aIIeIe. Ialienls vilh a CITR mulalion
vere younger lhan lhose vilh no mulalions (I 0.03). None had lhe combinalion of
sinouImonary disease, high sveal eIeclroIyle concenlralions, and Iov nasaI olenliaI-
difference vaIues lhal is diagnoslic of cyslic fibrosis.
SimiIarIy, Cohn el aI. (1998) sludied 27 alienls (mean age al diagnosis, 36 years), 22 of vhom
vere femaIe, vho had been referred for an evaIualion of idioalhic ancrealilis. DNA vas
lesled for 17 CITR mulalions and for lhe 5T aIIeIe in inlron 8. The 5T aIIeIe reduces lhe IeveI of
funclionaI CITR and is associaled vilh an inheriled form of inferliIily in maIes, CAVD. Cohn
el aI. (1998) found lhal 10 alienls vilh idioalhic chronic ancrealilis (37%) had al Ieasl 1
abnormaI CITR aIIeIe. Iighl CITR mulalions vere delecled. In 3 alienls bolh aIIeIes vere
affecled. These 3 alienls did nol have Iung disease lyicaI of cyslic fibrosis on lhe basis of
sveal lesling, siromelry, or base-Iine nasaI olenliaI-difference measuremenls. NonelheIess,
each had abnormaI nasaI cycIic AMI-medialed chIoride lransorl. The genolyes of lhe 3
alienls vere deII508/viIdlye (602421.0001), 9T/5T in 2, and deII508/R117H (602421.0005),
9T/7T in 1. These are lhe 2 mosl common genolyes in alienls vilh CAVD. These genolyes
do nol lyicaIIy cause Iung disease. In conlrasl, Iung disease is resenl in alienls vilh a
genolye of deII508/R117H, 9T/5T.
An abbrevialed lracl of 5T in inlron 8 of lhe CITR gene is found in aroximaleIy 10% of
individuaIs. To lesl vhelher lhe number of TG reeals ad|acenl lo 5T infIuences disease
enelrance, Groman el aI. (2004) delermined TG reeal number in 98 alienls vilh maIe
inferliIily due lo congenilaI absence of lhe vas deferens (277180), 9 alienls vilh noncIassic CI,
and 27 unaffecled individuaIs (ferliIe men). Iach of lhe individuaIs in lhis sludy had a severe
CITR mulalion on one CITR gene and 5T on lhe olher. Of lhe unaffecled individuaIs, 78% (21
of 27) had 5T ad|acenl lo 11 TG reeals, comared vilh 9% (10 of 107) of affecled individuaIs.
ConverseIy, 91% (97 of 107) of affecled individuaIs had 12 or 13 TG reeals, versus onIy 22% (6
of 27) of unaffecled individuaIs (I Iess lhan 0.00001). Those individuaIs vilh 5T ad|acenl lo
eilher 12 or 13 TG reeals vere subslanliaIIy more IikeIy lo exhibil an abnormaI henolye
lhan lhose vilh 5T ad|acenl lo 11 TG reeals (odds ralio 34.0, 95% CI 11.1-103.7.7, I Iess lhan
0.00001). Thus, delerminalion of TG reeal number viII aIIov for more accurale rediclion of
benign versus alhogenic 5T aIIeIes.
Lee el aI. (2003) haIolyed 117 Korean conlroIs and 75 CI alienls having bronchieclasis or
chronic ancrealilis using 11 oIymorhisms in CITR. SeveraI haIolyes, eseciaIIy lhose
vilh Q1352H (602421.0133), IVS8 T5 (602421.0086), and I217G (602421.0134), vere found lo
have disease associalions in a case-conlroI sludy. The common M470V oIymorhism
(602421.0023) aeared lo affecl lhe inlensily of lhe disease associalion. The T5-V470
haIolye shoved higher disease associalion lhan T5-M470, bul lhe Q1352H mulalion in a
V470 background shoved lhe slrongesl disease associalion. Nonsynonymous I217G and
Q1352H mulalions in lhe M470 background caused a 60 lo 80% reduclion in CITR-deendenl
chIoride currenls and bicarbonale lransorl aclivilies. The M470V oIymorhic varianl in
combinalion vilh lhe Q1352H mulalion comIeleIy aboIished CITR-deendenl anion
lransorl aclivilies. The resuIls reveaIed lhal inleraclions belveen muIliIe genelic varianls in
cis affecled lhe finaI funclion of lhe gene roducls.
uralli el aI. (2001) shoved lhal nucIear faclor TDI43 (605078) binds secificaIIy lo lhe UG
reeal sequence of CITR re-mRNA and, in lhis vay, romoles skiing of CITR exon 9.
Wang el aI. (2004) found lhal lhe mouse homoIog of human TDI43 aIso inhibils human CITR
exon 9 sIicing in a minigene syslem. uralli el aI. (2004) described exerimenls consislenl
vilh lhe modeI in vhich lhe TG reeals in lhe CITR inlron 8 bind lo TDI43, and lhis rolein,
in lurn, inhibils sIicing of exon 9. They suggesled lhal lheir resuIls rovide a mechanislic
exIanalion for lhe associalion dala of Groman el aI. (2004) and aIso an exIanalion for lhe
variabIe henolyic enelrance of lhe TG reeals. IndividuaI and lissue-secific variabiIily in
lhe concenlralion of lhis inhibilory sIicing faclor may even delermine vhelher an individuaI
viII deveIo muIlisyslemic (non-cIassic CI) or monosymlomalic (CAVD) disease.
Audrezel el aI. (2002) anaIyzed lhe enlire coding sequence and exon/inlron |unclions of lhe
CITR gene by denaluring high-erformance Iiquid chromalograhy (DHILC) and direcl
sequencing in 39 vhile Irench alienls vilh idioalhic chronic ancrealilis. A lolaI of 18
mulanl aIIeIes vere idenlified in 14 alienls (35.9%), among vhom 4 vere comound
helerozygoles. None of lhe 4 comound helerozygoles vere found lo have unrecognized CI-
reIaled uImonary symloms foIIoving reevaIualion. Hovever, a sveal lesl done
relrosecliveIy vas osilive in 2 of lhem. The 5T aIIeIe of lhe oIymorhic slring of
lhymidines al lhe end of inlron 8 of lhe CITR gene vas resenl in 7 of lhe 36 alienls lesled,
an aIIeIe frequency (9.7%) nearIy 2 limes grealer lhan lhe rale of 5% in lhe generaI ouIalion
(I 0.09).
The moIecuIar alhogenesis of cyslic fibrosis has been invesligaled by anaIysis of deII508
CITR in differenl heleroIogous syslems, reveaIing an abrogalion of CITR exression by
defeclive rolein maluralion. Mulanl CITR vas found arresled in an earIy viIdlye
inlermediale, unabIe lo adol a rolease-resislanl malure conformalion (Cheng el aI., 1990,
Gregory el aI., 1991, Zhang el aI., 1998) lhal enabIes exil from lhe endoIasmic relicuIum and
rocessing in lhe GoIgi comarlmenl. IroIonged inleraclion of immalure deII508 CITR vilh
lhe chaerones caInexin (CANX, 114217) and Hs70 (see 140550) in exerimenls by Iind el aI.
(1994) and Yang el aI. (1993), resecliveIy, indicaled lhal lhe aberranl rolein is recognized by
lhe ceII's quaIily conlroI and lhal remalure degradalion by lhe ubiquilin-roleasome
alhvay occurs in a re-GoIgi comarlmenl (}ensen el aI., 1995, Salo el aI., 1998). Reduclion of
lemeralure (Denning el aI., 1992) and addilion of chemicaI chaerones such as gIyceroI (Salo
el aI., 1996) and lrimelhyIamine-N-oxide (rovn el aI., 1996) overcame imedimenls in lhe
foIding alhvay of deII508 CITR and aIIoved roer largeling, lhus demonslraling lhal lhe
mulanl rolein is sliII caabIe of assuming a malure conformalion. Hovever, al lhe ceII
surface, lhe chIoride channeI formed lherefrom shoved a decreased haIf-Iife and reduced oen
robabiIily and sensilivily lo slimuIalion vilh cAMI agonisls.
KaIin el aI. (1999) invesligaled endogenous CITR exression in skin biosies and resiralory
and inleslinaI lissue secimens from deII508 homozygous alienls and non-CI ersons, using
immunohislochemicaI and immunobIol anaIyses vilh a aneI of CITR anlibodies. CITR
exression vas delecled al lhe IuminaI surface of reabsorlive sveal ducls and airvay
submucosaI gIands, al lhe aex of ciIialed ceIIs in seudoslralified resiralory eilheIia and of
isoIaled ceIIs of lhe viIIi of duodenum and |e|unum, and vilhin inlraceIIuIar comarlmenls of
inleslinaI gobIel ceIIs. In deII508 homozygous alienls, exression of lhe mulanl rolein
roved lo be lissue secific. Whereas deII508 CITR vas undeleclabIe in sveal gIands, lhe
exression in lhe resiralory and inleslinaI lracls couId nol be dislinguished from lhe
viIdlye by signaI inlensily or IocaIizalion. The lissue-secific varialion of deII508 CITR
exression from nuII lo aarenlIy normaI amounls indicaled lhal deII508 CITR maluralion
can be moduIaled and suggesled lhal delerminanls olher lhan CITR misIocaIizalion shouId
Iay a roIe in deII508 CI resiralory and inleslinaI disease.
WeIsh and Smilh (1993) rovided a cIassificalion of lhe mechanisms by vhich mulalions in
CITR cause cyslic fibrosis. The grouing of mulalions inlo 5 cIasses vas based on lheir
funclionaI effecl: (I) defeclive rolein roduclion, (II) defeclive rolein rocessing, (III)
defeclive rolein reguIalion, (IV) defeclive rolein conduclance, and (V) reduced amounls of
funclionaI CITR rolein. CIass I, II, and III mulalions have been associaled vilh lyicaI severe
muIliorgan disease on lhe basis of cIinicaI sludies. In conlrasl, cIass IV and V mulalions
aeared lo confer sufficienl funclionaI CITR lo resuIl in a miId henolye.
Haardl el aI. (1999) revieved lhe various cIasses of CI-associaled mulalions and added a
lenlalive addilionaI cIass VI. They suggesled lhal lhe mulalions can be groued inlo 2 ma|or
calegories. The firsl grou incIudes lhose mulanls lhal are unabIe lo accumuIale al lhe ceII
surface, eilher because of imaired biosynlhesis (cIass I and cIass V), or because of defeclive
foIding al lhe endoIasmic relicuIum (cIass II). Mulanls lhal beIong lo lhe second calegory are
exressed al lhe ceII surface bul faiI lo lransIocale chIoride ions because of a defecl in
aclivalion (cIass IV) or channeI conduclance (cIass III). ecause lhe biosynlhelic rocessing and
macroscoic chIoride channeI funclion of some of lhe lruncaled CITR conslrucls aear lo be
normaI bul lhe bioIogic slabiIily of lheir malure, comIex-gIycosyIaled form is dramalicaIIy
reduced, Haardl el aI. (1999) roosed a cIass VI, vhich vouId incIude slabiIily mulanls such
as lhose characlerized by lheir exerimenls.
To sludy lhe consequences lhal disease-causing mulalions have on lhe reguIalory funclion of
CITR, MickIe el aI. (2000) lransienlIy exressed CITR-bearing mulalions associaled vilh CI
or ils miIder henolye, congenilaI biIaleraI absence of lhe vas deferens (277180), and
delermined vhelher mulanl CITR couId reguIale oulvardIy reclifying chIoride channeIs
(ORCCs). CITR bearing a CI-associaled mulalion in lhe firsl nucIeolide-binding domain,
deIla-I508deI (602421.0001), funclioned as a chIoride channeI bul did nol reguIale ORCCs.
Hovever, CITR lhal had disease-associaled mulalions in olher domains relained bolh
funclions, regardIess of lhe associaled henolye. Thus, a reIalionshi belveen Ioss of CITR
reguIalory funclion and disease severily is evidenl for ND1, a region of CITR lhal aears
imorlanl for reguIalion of searale channeIs.
ronsveId el aI. (2001) delermined chIoride lransorl roerlies of lhe resiralory and
inleslinaI lracls in deIla-I508 lvins and sibs. In resiralory lissue, lhe exression of basaI
CITR-medialed chIoride conduclance, demonslraled by 30% of deIla-I508 homozygoles, vas
idenlified as a osilive rediclor of miIder CI. In inleslinaI lissue, 4,4-rime-
diisolhiocyanalosliIbene-2,2-rime-disuIfonic acid (DIDS)-insensilive chIoride secrelion, vhich
is indicalive of funclionaI CITR channeIs, correIaled vilh a miIder henolye, vhereas DIDS-
sensilive chIoride secrelion vas observed mainIy in more severeIy affecled alienls. ronsveId
el aI. (2001) concIuded lhal in deIla-I508 alienls, lhe abiIily lo secrele chIoride in lhe organs
lhal are rimariIy invoIved in lhe course of CI is rediclive of lhe CI henolye.
obadiIIa el aI. (2002) delermined lhe dislribulion of CITR mulalions in as many regions
lhroughoul lhe vorId as ossibIe in an efforl lo undersland lhe evoIulion of lhe disease in
each region and gain insighl for decisions regarding screening rograms. AIlhough vide
mulalionaI helerogeneily vas found lhroughoul lhe vorId, characlerizalion of lhe mosl
common mulalions in mosl ouIalions vas ossibIe. A significanl osilive correIalion vas
found belveen deIla-I508 frequency and lhe CI incidence of regionaI ouIalions.
Irimary scIerosing choIangilis (ISC, see 109720), a sIovIy rogressive choIeslalic Iiver disease
characlerized by fibroobIileralive infIammalion of lhe biIiary lracl, Ieads lo cirrhosis and orlaI
hyerlension and is a ma|or indicalion for Iiver lransIanlalion. Shelh el aI. (2003) slaled lhal
75 lo 80% of cases vere associaled vilh infIammalory boveI disease (ID, 266600) and lhal 2.5
lo 7.5% of alienls vilh ID deveIo ISC (Lee and KaIan, 1995). Shelh el aI. (2003)
hyolhesized lhal dysfunclion of CITR may exIain vhy a subsel of alienls vilh ID
deveIo ISC. They rosecliveIy evaIualed CITR genolye and henolye in 19 alienls vilh
ISC comared vilh 18 alienls vilh ID and no Iiver disease, 17 vilh rimary biIiary
cirrhosis (IC, 109720), 81 vilh CI, and 51 heaIlhy conlroIs. They found an increased
revaIence of CITR abnormaIilies in helerozygous slale in ISC as demonslraled by moIecuIar
and funclionaI anaIyses, and concIuded lhal lhese abnormaIilies may conlribule lo lhe
deveIomenl of ISC in a subsel of alienls vilh ID. Iighly-nine ercenl of ISC alienls
carried genolyes conlaining lhe 1540G varianl (602421.0023) resuIling in decreased funclionaI
CITR comared vilh 57% of disease conlroIs (I 0.03). OnIy 1 of 19 ISC alienls had neilher
a CITR mulalion nor lhe 1540G varianl. CITR chIoride channeI funclion assessed by nasaI
olenliaI difference lesling demonslraled a reduced median isorolerenoI resonse in ISC
alienls comared vilh disease conlroIs and heaIlhy conlroIs.
Iagani el aI. (2003) shoved lhal severaI nucIeolide changes in exon 12 of lhe CITR gene
induced a variabIe exlenl of exon skiing, Ieading lo reduced IeveIs of normaI lranscrils.
This vas lhe case in 2 naluraI mulalions--1 of vhich vas gIy576 lo aIa (G576A, 602421.0061),
vhich had reviousIy been considered a neulraI oIymorhism--and severaI sile-direcled
siIenl subslilulions. This henomenon vas due lo lhe inlerference vilh a reguIalory eIemenl,
vhich lhe aulhors named comosile exonic reguIalory eIemenl of sIicing (CIRIS). The effecl
of singIe-nucIeolide subslilulions al CIRIS couId nol be redicled by eilher serine-arginine-
rich (SR) malrices or enhancer idenlificalion. Iagani el aI. (2003) suggesled lhal aroriale
funclionaI sIicing assays shouId be incIuded in genolye screenings lo dislinguish belveen
oIymorhisms and alhogenic mulalions.
y lesling 19 synonymous changes in nucIeolides 13 lo 52 of lhe human CITR exon 12, Iagani
el aI. (2005) found lhal lhe robabiIily of inducing exon skiing vilh a singIe synonymous
subslilulion vas aroximaleIy 30%, demonslraling lhal synonymous subslilulions can affecl
sIicing and are nol neulraI in evoIulion as lhey can be conslrained by sIicing requiremenls.
Iagani el aI. (2005) suggesled lhal evoIulionary seIeclion of genomic varialion lakes Iace al 2
sequenliaI IeveIs: sIicing conlroI and rolein funclion olimizalion.
Aznarez el aI. (2003) invesligaled lhe consequence of 2 CI disease-causing mulalions on lhe
funclion of a ulalive exonic sIicing enhancer (ISI) in exon 13 of lhe CITR gene. olh
mulalions caused aberranl sIicing in a redicled manner, suorling a roIe for lhe ulalive
ISI sequence in re-mRNA sIicing. In addilion, 3 mulalions, incIuding D648V (602421.0097),
caused aberranl sIicing of exon 13 by imroving lhe oIyyrimidine lracls of 2 crylic 3-
rime sIice siles. The reIalive IeveIs of 2 sIicing faclors, Tra2-aIha (TRA2A, 602718) and
SI2/ASI (SIRS1, 600812), aIlered lhe effecl on sIicing of some of lhe exon 13 disease
mulalions. The aulhors suggesled lhal lhe severily of CI may be moduIaled by changes in lhe
fideIily of CITR re-mRNA sIicing.
Audrezel el aI. (2004) reorled lhe firsl syslemalic screening of lhe 27 exons of lhe CITR gene
for Iarge genomic rearrangemenls, by means of lhe quanlilalive muIliIex ICR of shorl
fIuorescenl fragmenls (QMISI). AIlhough many disease aIIeIes of CITR had reviousIy been
idenlified, u lo 30% of disease aIIeIes sliII remained lo be idenlified in some ouIalions, and
il had been suggesled lhal gross genomic rearrangemenls couId accounl for lhese unidenlified
aIIeIes. Audrezel el aI. (2004) sludied a veII-characlerized cohorl of 39 alienls vilh cIassic CI
carrying al Ieasl 1 unidenlified aIIeIe. Using QMISI, aroximaleIy 16% of lhe reviousIy
unidenlified CI mulanl aIIeIes vere idenlified and characlerized, incIuding 5 noveI mulalions
(1 Iarge deIelion and 4 inserlions/deIelions). The breakoinls of lhese 5 mulalions vere
reciseIy delermined. AIlhough nonhomoIogous recombinalion may be invoked lo exIain aII
5 comIex Iesions, each mulalion aeared lo have arisen lhrough a differenl mechanism. One
of lhe inserlions/deIelions vas highIy unusuaI in lhal il invoIved lhe inserlion of a shorl 41-b
sequence vilh arliaI homoIogy lo a relrolransosilionaIIy-comelenl LINI-1 eIemenl.
Audrezel el aI. (2004) suggesled lhal lhe inserlion of lhis uIlra-shorl LINI-1 eIemenl (dubbed a
'hyhen eIemenl') may conslilule a noveI lye of mulalion associaled vilh human genelic
disease.
DinucIeolide reeals are ubiquilous fealures of eukaryolic genomes. The highIy variabIe
nalure of dinucIeolide reeals makes lhem arlicuIarIy inleresling candidales for modifiers of
RNA sIicing vhen lhey are found near sIicing signaIs. An examIe of a variabIe
dinucIeolide reeal lhal affecls sIicing is a TG reeal Iocaled in lhe sIice accelor of exon 9
of lhe CITR gene. Higher reeal numbers resuIl in reduced exon 9 sIicing efficiency and, in
some inslances, lhe reduclion in fuII-Ienglh lranscril is sufficienl lo cause maIe inferliIily due
lo congenilaI biIaleraI absence of lhe vas deferens (277180) or noncIassic cyslic fibrosis. Using a
CITR minigene syslem, Hefferon el aI. (2004) sludied TG lracl varialion and observed lhe
same correIalion belveen dinucIeolide reeal number and exon 9 sIicing efficiency seen in
vivo. IIacemenl of lhe TG dinucIeolide lracl in lhe minigene vilh random sequence aboIished
sIicing of exon 9. ReIacemenl of lhe TG lracl vilh sequences lhal can seIf-baseair suggesled
lhal lhe formalion of an RNA secondary slruclure vas associaled vilh efficienl sIicing,
hovever, sIicing efficiency vas inverseIy correIaled vilh lhe redicled lhermodynamic
slabiIily of such slruclures, demonslraling lhal inlermediale slabiIily vas olimaI. IinaIIy,
subslilulion vilh TA reeals of differing Ienglh confirmed lhal slabiIily of lhe RNA secondary
slruclure, nol sequence conlenl, correIaled vilh sIicing efficiency. Hefferon el aI. (2004)
concIuded lhal dinucIeolide reeals can form secondary slruclures lhal have variabIe effecls
on RNA sIicing efficiency and cIinicaI henolye.
Wong el aI. (2003) described ancrealic-insufficienl CI in a chiId vhose falher vas from
Taivan and molher from Vielnam. The chiId had 2 differenl nuII mulalions, gIu7 lo ler
(602421.0131) in exon 1 and a 1-b inserlion, 989A (602421.0132), vhich caused frameshifl and
a lruncaled CITR rolein of 306 amino acids. Wong el aI. (2003) commenled on lhe facl lhal
Iasl Asian CI alienls did nol share mulalions vilh alienls of olher elhnic backgrounds.
Iven vilhin Iasl Asians, lhe CITR mulalion seclrum in Chinese alienls is dislincl from lhal
of }aanese alienls.
Chang el aI. (2007) idenlified mulalions in lhe CITR gene in 14.1% of lolaI aIIeIes and 24.4% of
78 Chinese/Taivanese alienls vilh idioalhic chronic ancrealilis (ICI, 167800) comared lo
4.8% of lolaI aIIeIes and 9.5% of 200 malched conlroIs. The findings indicaled lhal
helerozygous carriers of CITR mulalions have an increased risk of deveIoing ICI. The
mulalions idenlified vere differenl from lhose usuaIIy observed in Weslern counlries. The T5
aIIeIe vilh 12 or 13 TG reeals vas significanlIy associaled vilh earIier age al onsel in alienls
vilh ICI, aIlhough lhe frequency of lhis aIIeIe did nol differ belveen alienls and conlroIs.
Sun el aI. (2006) anaIyzed lhe oIymorhic TG dinucIeolide reeal ad|acenl lo lhe 5T varianl in
inlron 8 and lhe codon 470 in exon 10. Ialienls seIecled for lhis sludy vere osilive for bolh
lhe 5T varianl and lhe ma|or cyslic fibrosis mulalion, deIla-I508. AImosl aII deIla-I508
mulalions occur in a 10TG-9T-470M haIolye. Therefore, il is ossibIe lo delermine lhe
haIolye of lhe 5T varianl in lrans. Of lhe 74 samIes anaIyzed, 41 (55%) vere 11TG-5T-
470M, 31 (42%) vere 12TG-5T-470V, and 2 (3%) vere 13TG-5T-470M. Of lhe 49 cases for vhich
lhey had cIinicaI informalion, Sun el aI. (2006) reorled lhal 17.6% of femaIes (6 of 34) and
66.7% of maIes (10 of 15) shoved symloms resembIing alyicaI cyslic fibrosis. The haIolye
vilh lhe highesl enelrance in femaIes (42%, or 5 of 12) and more lhan 80% (5 of 6) in maIes
vas 12TG-5T-470V. The aulhors aIso evaIualed 12 maIes affecled vilh congenilaI biIaleraI
absence of vas deferens and osilive for lhe 5T varianl, 10 of 12 had lhe 12TG-5T-470V
haIolye. Sun el aI. (2006) concIuded lhal overaII, lhe 5T varianl has a miIder cIinicaI
consequence lhan reviousIy eslimaled in femaIes. The cIinicaI resenlalions of lhe 5T varianl
are associaled vilh lhe 5T-12TG-470M haIolye.
AIonso el aI. (2006) anaIyzed 1,954 Sanish cyslic fibrosis aIIeIes lo define lhe moIecuIar
seclrum of mulalions. CommerciaI aneIs shoved a Iimiled deleclion over, Ieading lo lhe
idenlificalion of onIy 76% of aIIeIes. More sensilive assays idenlified 12 mulalions vilh
frequencies above 1%, lhe I508deI mulalion being lhe mosl frequenl, resenl on 51% of aIIeIes.
In lhe Sanish ouIalion, 18 mulalions vere needed lo achieve a deleclion rale of 80%. Iifly-
one mulalions (42%) vere observed once. AIonso el aI. (2006) idenlified a lolaI of 121 disease-
causing mulalions lhal accounled for 96% of CI aIIeIes.
KLL+:7%)L%&09-)82/:)B9,+%&-7919)79:B
In addilion lo lheir anlimicrobiaI aclivily, aminogIycoside anlibiolics can suress remalure
lerminalion codons by aIIoving an amino acid lo be incororaled in Iace of lhe slo codon,
lhus ermilling lransIalion lo conlinue lo lhe normaI end of lhe lranscril. The mechanism
lransIalion lerminalion is highIy conserved among mosl organisms and is aImosl aIvays
signaIed by an amber (UAG), ochre (UAA), or oaI (UGA) lerminalion codon. The nucIeolide
sequence surrounding lhe lerminalion codon has an imorlanl roIe in delermining lhe
efficiency of lransIalion lerminalion. AminogIycoside anlibiolics can reduce lhe fideIily of
lransIalion, redominanlIy by inhibiling ribosomaI 'roofreading,' a mechanism lo excIude
oorIy malched aminoacyI-lRNA from becoming incororaled inlo lhe oIyelide chain. In
lhis vay aminogIycosides increase lhe frequency of erroneous inserlions al lhe nonsense
codon and ermil lransIalion lo conlinue lo lhe end of lhe gene, as has been shovn in
eukaryolic ceIIs (urke and Mogg, 1985), incIuding human fibrobIasls (uchanan el aI., 1987).
Hovard el aI. (1996) demonslraled lhal 2 CITR-associaled slo mulalions couId be
suressed by lrealing ceIIs vilh Iov doses of an aminogIycoside anlibiolic. Olhers
demonslraled lhis effecl in cuIlured ceIIs bearing CITR nonsense mulalions and in conneclion
vilh slo mulalions in muscuIar dyslrohy in mice and in vilro in HurIer syndrome (607014),
cyslinosis (219800), and olher disorders.
In a CI bronchiaI ceII Iine carrying lhe CITR W1282X (602421.0022) mulalion, edveII el aI.
(1997) demonslraled lhal lrealmenl vilh lhe aminogIycosides G418 and genlamicin reslored
CITR exression, as shovn by lhe reaearance of cAMI-aclivaled chIoride currenls, lhe
resloralion of CITR rolein al lhe aicaI Iasma membrane, and an increase in lhe abundance
of CITR mRNA IeveIs from lhe W1282X aIIeIe.
WiIschanski el aI. (2003) erformed a doubIe-bIind Iacebo-conlroIIed crossover lriaI of
inlranasaI genlamicin in alienls vilh slo mulalions in CITR, in comarison vilh alienls
homozygous for lhe deIla-I508 mulalion. NasaI olenliaI difference vas measured al baseIine
and afler each lrealmenl. Genlamicin lrealmenl caused a significanl reduclion in basaI
olenliaI difference in 19 alienls carrying slo mulalions and a significanl resonse lo
chIoride-free isorolerenoI soIulion. This effecl of genlamicin on nasaI olenliaI difference
occurred bolh in alienls vho vere homozygous for slo mulalions and in lhose vho vere
helerozygous, bul nol in alienls vho vere homozygous for deIla-I508. Afler genlamicin
lrealmenl, a significanl increase in eriheraI and surface slaining for CITR vas observed in
Anima! Mndc!
Tala el aI. (1991) cIoned lhe mouse homoIog of lhe human CITR gene.
McCombie el aI. (1992) used exressed sequence lags lo idenlify homoIogs of human genes,
incIuding CITR and lhe LDL recelor gene (606945), in Caenorhabdilis eIegans. They
suggesled lhal C. eIegans, because of lhe exlensive informalion on lhe hysicaI and genelic
ma of lhe organism, mighl have unique advanlages for lhe sludy of lhe funclion of normaI
and mulanl genes. The same aroach vas aIied even more exlensiveIy by Walerslon el aI.
(1992) vho, by sludy of a cDNA Iibrary, idenlified aboul 1,200 of lhe eslimaled 15,000 genes of
C. eIegans. More lhan 30% of lhe inferred rolein sequences had significanl simiIarily lo
exisling sequences in dalabases.
Zeiher el aI. (1995) noled lhal lhe I508deI (602421.0001) mulalion disruls lhe biosynlhelic
rocessing of CITR so lhal lhe rolein is relained in lhe endoIasmic relicuIum and is lhen
degraded. As a resuIl, affecled eilheIia Iack CITR in lhe aicaI membrane and Iack cAMI-
slimuIaled chIoride ion ermeabiIily. Dorin el aI. (1992) and Snouvaerl el aI. (1992), as veII as
olhers, disruled lhe mouse CITR gene lo creale nuII mulanl mice lhal Iack CITR or exress
grealIy reduced amounls of viIdlye rolein. To undersland lhe alhohysioIogy of lhe
disease and lo evaIuale nev lheraies, Zeiher el aI. (1995) used a largeling slralegy lo
inlroduce lhe I508deI mulalion inlo lhe mouse CITR gene. Murine CITR is 78% idenlicaI lo
human CITR, and il conlains a henyIaIanine al residue 508 fIanked by 28 amino acids
idenlicaI lo lhose in human CITR. They couId shov lhal affecled eilheIia from homozygous
I508deI mice Iacked CITR in lhe aicaI membrane and vere chIoride ion-imermeabIe. Iorly
ercenl of homozygous animaIs survived inlo aduIlhood and disIayed severaI abnormaIilies
found in human disease and in CITR nuII mice.
Van Doorninck el aI. (1995) generaled a mouse modeI of CI vilh lhe he508deI mulalion
using lhe 'hil-and-run' mulagenesis rocedure. In lhis modeI, lhe inlron slruclure vas nol
dislurbed, in conlrasl lo simiIar modeIs (Zeiher el aI., 1995, CoIIedge el aI., 1995). Irench el aI.
(1996) demonslraled lhal in lhis modeI of CI lhe mulanl CITR vas nol rocessed efficienlIy lo
lhe fuIIy gIycosyIaled form in vivo. Hovever, lhe mulanl rolein vas exressed as funclionaI
chIoride channeIs in lhe Iasma membrane of ceIIs cuIlured al reduced lemeralure.
Iurlhermore, lhey couId shov lhal lhe eIeclrohysioIogic characlerislics of lhe mouse
he508deI-CITR channeIs vere indislinguishabIe from normaI. In homozygous mulanl mice
lhey did nol observe a significanl effecl of genelic background on lhe IeveI of residuaI chIoride
channeI aclivily. The dala shoved lhal Iike ils human homoIog, lhe mouse mulanl CITR is a
lemeralure-sensilive rocessing mulanl, and lherefore an aulhenlic modeI for sludy of
alhohysioIogy and lheray.
Dickinson el aI. (2002) reIicaled lhe G480C mulalion (602421.0083) in lhe murine Cflr gene
using lhe 'hil-and-run' doubIe recombinalion rocedure. The G480C cyslic fibrosis mouse
modeI exressed lhe G480C mulanl lranscril al a IeveI comarabIe lo lhal of viIdlye Cflr.
The homozygous mulanl mice vere ferliIe and had normaI survivaI, veighl, loolh coIor, and
no evidence of cecaI bIockage, desile miId gobIel ceII hyerlrohy in lhe inlesline. AnaIysis
of lhe mulanl rolein reveaIed lhal lhe ma|orily of G480C CITR vas abnormaIIy rocessed
and no G480C CITR-secific immunoslaining in lhe aicaI membranes of inleslinaI ceIIs vas
delecled. The bioeIeclric henolye of lhese mice reveaIed organ-secific eIeclrohysioIogicaI
effecls. In conlrasl lo deIla-I508 'hil-and-run' homozygoles, lhe cIassic defecl of forskoIin-
induced chIoride ion lransorl vas nol reIicaled in lhe cecum, bul lhe resonse lo Iov
chIoride in lhe nose vas cIearIy defeclive in lhe G480C mulanl animaIs.
Of imorlance lo any gene-reIacemenl slralegy for lrealmenl of CI is lhe idenlificalion of lhe
ceII lye(s) vilhin lhe Iung miIieu lhal need lo be correcled and an indicalion vhelher lhis is
sufficienl lo reslore a normaI infIammalory resonse and bacleriaI cIearance. Oceandy el aI.
(2002) generaled G551D CI mice lransgenicaIIy exressing lhe human CITR gene in 2 lissue
comarlmenls reviousIy demonslraled lo mediale a CITR-deendenl infIammalory
resonse: Iung eilheIium and aIveoIar macrohages. IoIIoving chronic uImonary infeclion
vilh Iseudomonas aeruginosa, CI mice vilh eilheIiaI-exressed (bul nol macrohage-
secific) CITR shoved an imrovemenl in alhogen cIearance and infIammalory markers
comared vilh conlroI CI animaIs. The aulhors concIuded lhal lhere may be a roIe for CITR-
medialed evenls in eilheIiaI ceIIs in resonse of lhe Iung lo bacleriaI alhogens.
Di el aI. (2006) found lhal aIveoIar macrohages from Cflr -/- mice relained lhe abiIily lo
hagocylose and generale an oxidalive bursl, bul exhibiled defeclive kiIIing of inlernaIized
bacleria. Lysosomes from Cflr -/- macrohages faiIed lo acidify, aIlhough lhey relained normaI
fusogenic caacily vilh nascenl hagosomes. Di el aI. (2006) roosed lhal CITR conlribules
lo Iysosome acidificalion and lhal in ils absence hagoIysosomes acidify oorIy, lhus
roviding an environmenl conducive lo bacleriaI reIicalion.
The deIla-I508 CITR mulalion resuIls in lhe roduclion of a misfoIded CITR rolein lhal is
relained in lhe endoIasmic relicuIum and largeled for degradalion. Curcumin, a ma|or
comonenl of lhe curry sice lurmeric, is a nonloxic caIcium-adenosine lrihoshalase um
inhibilor lhal can be adminislered lo humans safeIy. Igan el aI. (2004) found lhal oraI
adminislralion of curcumin lo homozygous deIla-I508 Cflr mice in doses comarabIe, on a
veighl-er-veighl basis, lo lhose veII loIeraled by humans correcled lhese animaIs'
characlerislic nasaI olenliaI difference defecl. These effecls vere nol observed in mice
homozygous for a comIele knockoul of lhe CITR gene. Curcumin aIso induced lhe funclionaI
aearance of deIla-I508 CITR rolein in lhe Iasma membranes of lransfecled baby hamsler
kidney ceIIs. Igan el aI. (2004) concIuded lhal curcumin lrealmenl may be abIe lo correcl
defecls associaled vilh lhe homozygous exression of lhe deIla-I508 CITR gene, as il aIIovs
for dissocialion from IR chaerone roleins and lransfer lo lhe ceII membrane.
DeIayed uberly is common among individuaIs vilh cyslic fibrosis and is usuaIIy allribuled lo
chronic disease and/or oor nulrilion. Hovever, deIayed uberly has been reorled as a
fealure of CI even in lhe selling of good nulrilionaI and cIinicaI slalus (}ohannesson el aI.,
1997). This finding, aIong vilh evidence lhal Cflr is exressed in ral brain, human
hyolhaIamus, and a gonadolroin-reIeasing hormone secreling Iine, raised lhe ossibiIily
lhal some of lhe uberlaI deIay in cyslic fibrosis couId slem direclIy from aIleralions in Cflr
funclion lhal affecls lhe hyolhaIamic-iluilary-gonadaI axis. To examine lhis hyolhesis, }in
el aI. (2006) sludied uberlaI liming in a mouse modeI of CI engineered lo roduce a
lruncaled Cflr mRNA and referred lo as S489X. Homozygous knockoul mice, vhich have
chronic infIammalion and gaslroinleslinaI disease, grev more sIovIy and had Ialer onsel of
uberly lhan viIdlye animaIs. }in el aI. (2006) anlicialed lhal lhe knockoul helerozygoles,
vhich have no cIinicaI CI henolye, mighl disIay an inlermediale liming of uberly. They
found, hovever, lhal lhese mice had earIier onsel of uberly, as assessed by vaginaI oening
(VO), lhan viIdlye. These findings vere confirmed in a second indeendenl modeI of CI
engineered lo generale lhe deIla-I508 mulalion in mice. Again lhe homozygoles disIayed
Ialer uberlaI liming, and lhe helerozygoles disIayed earIier VO lhan lhe viIdlye animaIs.
These dala rovided furlher evidence lhal Cflr can direclIy moduIale lhe reroduclive
endocrine axis and raised lhe ossibiIily lhal helerozygole mulalion carriers may have a
reroduclive advanlage.
Ior furlher informalion on animaI modeIs for CI, see 219700.
ALLELIC VARIANT5 (5c!cctcd Examp!cs):
TabIe Viev
.0001 CY5TIC FIBRO5I5
RONCHIICTASIS WITH OR WITHOUT ILIVATID SWIAT CHLORIDI 1, MODIIIIR OI,
INCLUDID
CITR, IHI508DIL
DeIelion of 3 baseairs in exon 10 Ieads lo deIelion of henyIaIanine al codon 508 (deIla-I508)
(Kerem el aI., 1989). The Iuroean Working Grou on CI Genelics (1990) ubIished
informalion on lhe dislribulion of lhe deIla-I508 mulalion in Iuroe. The dala, iIIuslraled
vilh a usefuI ma, indicaled a slriking cIine across Iuroe from Iov vaIues of 30% in lhe
soulheasl (in Turkey) lo high vaIues in lhe norlhvesl (e.g., 88% in Denmark). The grou
suggesled lhal lhe sread of lhe CI gene mighl have accomanied lhe migralions of earIy
farmers slarling from lhe MiddIe Iasl and sIovIy rogressing lovard lhe norlhvesl of
Iuroe. The diffusion of lhe gene may have been favored by lhe seIeclive advanlage conferred
by lhe gene. Slrong associalion vilh lhe so-caIIed haIolye vas demonslraled. The
ossibiIily of 'hilchhiking,' i.e., lhe infIuence of neighboring genes vas discussed. Rozen el aI.
(1990) found lhe deIla-I508 mulalion in 71% of CI chromosomes from urban Quebec rovince
Irench-Canadian famiIies, 55% of lhose from Saguenay-Lac Sl. }ean region famiIies and in 70%
of lhose from Louisiana Acadian famiIies. De raekeIeer (1991) eslimaled lhal lhe frequency al
birlh of cyslic fibrosis is 1/926 in lhe Saguenay-Lac Sl. }ean region, giving a carrier rale of 1/15.
Ior lhe same region, DaigneauIl el aI. (1991) reorled a revaIence of CI al birlh of 1/902
Iiveborns, and a carrier rale of 1/15. Rozen el aI. (1992) found lhal lhe deIla-I508 mulalion vas
resenl in 58% of Saguenay-Lac Sl. }ean CI famiIies, vilh lhe G-lo-T donor sIice sile
mulalion afler codon 621 being found in 23%, and lhe A455I mulalion (602421.0007) in 8%.
The Ialler 2 mulalions vere nol found in urban Quebec famiIies. This rovided furlher
evidence of lhe roIe of founder effecl. Among 293 alienls, Kerem el aI. (1990) found lhal lhose
vho vere homozygous for lhe I508 deIelion had received a diagnosis of cyslic fibrosis al an
earIier age and had a grealer frequency of ancrealic insufficiency. Iancrealic insufficiency
vas resenl in 99% of lhe homozygous alienls, 72% of lhose helerozygous for lhe deIelion,
and onIy 36% of alienls vilh olher mulalions. Waulers el aI. (1991) sludied lhe frequency of
lhe deIla-I508 mulalion among eIgian alienls vilh CI. The mulalion vas resenl in 80% of
CI chromosomes from 36 unreIaled famiIies. Ninely-lhree ercenl of lhe CI chromosomes
carrying lhe deIla-I508 mulalion aIso carried haIolye in lhis ouIalion. GiIIe el aI. (1991)
described a slralegy for efficienl helerozygole screening for lhe deIla-I508 mulalion. They
shoved lhal ICR couId delecl a helerozygole in a ooI of u lo 49 unreIaled DNA samIes.
Lerer el aI. (1992) reorled lhal lhe deIla-I508 mulalion accounls for 33.8% of }evish CI
aIIeIes.
The asque ouIalion is lhoughl lo be one of lhe oIdesl in Iuroe, having been eslabIished in
veslern Iuroe during lhe Iale IaIeoIilhic Age. Iuskera, lhe asque Ianguage, is lhoughl lo be
re-Indo-Iuroean, originaling from lhe firsl sellIers of Iuroe. The variabIe dislribulion of
lhe deII508 mulalion in Iuroe, vilh higher frequencies in norlhern Iuroe and Iover
frequencies in soulhern Iuroe, has been allribuled lo a sread of lhe mulalion by earIy
farmers migraling from lhe MiddIe Iasl during lhe NeoIilhic eriod. Hovever, a very high
frequency of lhis mulalion vas found in lhe asque Irovinces, vhere lhe incidence of CI is
aroximaleIy 1 in 4,500. In a sludy of 45 CI famiIies from lhe asque Irovinces, CasaIs el aI.
(1992) found lhal lhe frequency of lhe deII508 mulalion vas 87% in lhe chromosomes of
individuaIs of ure asque exlraclion and 58% in lhose of mixed asque origin. CasaIs el aI.
(1992) roosed lhal lhe deII508 mulalion vas resenl in Iuroe more lhan 10,000 years ago,
receding lhe agricuIluraI migralions vhich diIuled lhe mulalion ralher lhan inlroducing il.
aIIabio el aI. (1990) described an aIIeIe-secific amIificalion melhod for diagnosing lhe
henyIaIanine-508 deIelion. Among IuebIo and Nava|o Nalive Americans of lhe U.S.
Soulhvesl, Grebe el aI. (1992) found no inslance of lhe deII508 mulalion in 12 affecled
individuaIs. CIinicaIIy, 6 of lhe affecled individuaIs had grovlh deficiency and 5 (aII from lhe
Zuni IuebIo) had a severe CI henolye. Iour of lhe 6 Zunis vilh CI vere aIso
microcehaIic, a finding nol reviousIy noled in CI alienls. In an anaIysis of 640 Sanish
cyslic fibrosis famiIies, CasaIs el aI. (1997) found lhal 75 mulalions accounled for 90.2% of CI
chromosomes - an exlraordinariIy high helerozygosily. The frequency of lhe deIla-I508
mulalion vas 53.2%. The nexl mosl frequenl mulalion vas gIy542 lo ler (602421.0009) vilh a
frequency of 8.43%.
Using 3 inlragenic microsaleIIiles of lhe CITR gene Iocaled in inlrons, Russo el aI. (1995)
evaIualed Iinkage disequiIibrium belveen each marker and various CI mulalions on a lolaI of
377 CI and 358 normaI chromosomes from IlaIian sub|ecls. ResuIls vere considered consislenl
vilh lhe hyolhesis lhal aII deI508 chromosomes derived from a singIe mulalionaI evenl. The
same hyolhesis vas vaIid for 3 olher mulalions vhich mighl have originaled more recenlIy
lhan deI508.
Grebe el aI. (1994) erformed moIecuIar genelic anaIyses on 129 Hisanic individuaIs vilh
cyslic fibrosis in lhe soulhveslern Uniled Slales. OnIy 46% (59 of 129) carried mulalion
I508deI (frequency in lhe generaI ouIalion 67.1%).
In 69 IlaIian alienls vilh CI due lo homozygosily for lhe deII508 mulalion, De Rose el aI.
(2005) found lhal lhose vho aIso carried lhe R131 aIIeIe of lhe immunogIobuIin Ic-gamma
recelor II gene (ICGR2A, see 146790.0001) had a 4-foId increased risk of acquiring chronic
Iseudomonas aeruginosa infeclion ( 0.042). De Rose el aI. (2005) suggesled lhal ICGR2A
Iocus variabiIily conlribules lo lhis infeclion suscelibiIily in CI alienls.
In a 62-year-oId voman vilh idioalhic bronchieclasis (ISC1, 211400) and eIevaled sveal
chIoride bul normaI nasaI olenliaI difference, vho carried a helerozygous I508deI CITR
mulalion, Ia|ac el aI. (2008) aIso idenlified helerozygosily for a missense mulalion in lhe
SCNN1 gene (600760.0015). The alienl had a forced exiralory voIume in 1 second (IIV1)
lhal vas 89% of redicled. Ia|ac el aI. (2008) concIuded lhal varianls in SCNN1 may be
deIelerious for sodium channeI funclion and Iead lo bronchieclasis, eseciaIIy in alienls vho
aIso carry a mulalion in lhe CITR gene.
Okiyoneda el aI. (2010) idenlified lhe comonenls of lhe eriheraI rolein quaIily conlroI
nelvork lhal removes unfoIded CITR conlaining lhe I508deI mulalion from lhe Iasma
membrane. ased on lheir resuIls and roleoslalic mechanisms al differenl subceIIuIar
Iocalions, Okiyoneda el aI. (2010) roosed a modeI in vhich lhe recognilion of unfoIded
cyloIasmic regions of CITR is medialed by HSC70 (600816) in concerl vilh DNA}A1 (602837)
and ossibIy by lhe HSI90 machinery (140571). IroIonged inleraclion vilh lhe chaerone-
cochaerone comIex recruils CHII (607207)-UCH5C (602963) and Ieads lo ubiquilinalion of
conformalionaIIy damaged CITR. This ubiquilinalion is robabIy infIuenced by olher I3
Iigases and deubiquilinaling enzyme aclivilies, cuIminaling in acceIeraled endocylosis and
IysosomaI deIivery medialed by Ub-binding cIalhrin adalors and lhe endosomaI sorling
comIex required for lransorl (ISCRT) machinery, resecliveIy. In an accomanying
erseclive, Hull and aIch (2010) commenled lhal lhe 'yin-yang' baIance mainlained by lhe
roleoslasis nelvork is crilicaI for normaI ceIIuIar, lissue, and organismaI hysioIogy.
CITR, ILI507DIL
DeIelion of isoIeucine al eilher osilion 506 or 507 is lhe resuIl of deIelion of 3 b (deIla-I507)
(Kerem el aI., 1990). NeIson el aI. (1991) found lhe same mulalion in homozygous slale in 2
sibs vilh severe ancrealic insufficiency. Orozco el aI. (1994) commenled on lhe difficuIlies in
recognizing lhe iIe507-lo-deI mulalion in a comound helerozygole vilh I508deI.
CITR, GLN493TIR |dbSNI:rs77101217j
A C-lo-T change in nucIeolide 1609 in exon 10 is resonsibIe for a slo mulalion al osilion
493 (Q493X) (Kerem el aI., 1990).
CITR, ASI110HIS |dbSNI:rs113993958j
Using lhe melhod for idenlifying singIe-slrand conformalion oIymorhisms (SSCIs)
deveIoed by Orila el aI. (1989), Dean el aI. (1990) idenlified 3 differenl mulalions associaled
vilh miId cyslic fibrosis. AII 3 mulalions reIaced charged amino acids vilh Iess oIar
residues and resuIled in changes in lhe ulalive lransmembrane seclions of lhe moIecuIe. The
mulaled amino acids vere found lo be ones conserved in bolh rodenls and amhibians and lo
Iie in a region of CITR lhal is beIieved lo form a channeI in lhe membrane. In a famiIy
idenlified as OS-7, a C-lo-G lransversion in exon 4 reIaced an asarlic acid residue vilh
hislidine (D110H). (The Orila melhod for idenlifying SSCIs invoIves amIificalion of 100-400
b segmenls of radioIabeIed DNA, vhich are subsequenlIy denalured and eIeclrohoresed on
high resoIulion, nondenaluring acryIamide geIs. Under lhese condilions each slrand of lhe
DNA fragmenl can foId back on ilseIf in a unique conformalion. Mulalions vilhin a DNA
segmenl viII oflen aIler lhe secondary slruclure of lhe moIecuIe and affecl ils eIeclrohorelic
mobiIily.)
VAS DIIIRINS, CONGINITAL ILATIRAL ASINCI OI, INCLUDID
CITR, ARG117HIS |dbSNI:rs78655421j
In 2 resumabIy unreIaled famiIies vilh miId CI, Dean el aI. (1990) found a 482G-A lransilion
in exon 4 of lhe CITR gene, resuIling in an arg117-lo-his (R117H) subslilulion.
Gervais el aI. (1993) reorled lhal lhe R117H mulalion vas resenl in 4 of 23 alienls vilh
congenilaI absence of lhe vas deferens (CAVD, 277180). Three alienls had comound
helerozygosily for R117H and deII508, vhereas a fourlh vas a comound helerozygole for
R117H and 2322deIG. None of lhe 23 alienls had uImonary evidence of cyslic fibrosis. Iive
alienls vilhoul lhe deII508 mulalion had uniIaleraI renaI agenesis in addilion lo absence of
lhe vas deferens, lhese alienls may reresenl a differenl dislincl subsel. ienvenu el aI. (1993)
described for lhe firsl lime homozygosily for lhe R117H mulalion in a 30-year-oId Irench maIe
vilh sleriIily oving lo congenilaI biIaleraI absence of lhe vas deferens. The sub|ecl had no
resiralory or ancrealic invoIvemenl and had a normaI sveal eIeclroIyle vaIue. His arenls
vere nol consanguineous, and lhere vere no olher cases of CAVD or CI in lhe famiIy.
Kieseveller el aI. (1993) resenled evidence lhal lhe chromosome background of lhe R117H
mulalion has a rofound effecl on lhe henolye roduced. Three Ienglh varianls of CITR
have been observed vilh varying degrees of exon 9 sIicing deending on varialion in lhe
Ienglh of lhe oIyyrimidine lracl in lhe sIice accelor sile in inlron 8 (Chu el aI., (1991,
1993)). Varied Ienglhs of a lhymidine (T)-lracl (5, 7, or 9Ts) vere noled in fronl of lhe sIice
accelor sile of inlron 8. The 5T varianl is resenl in 5% of lhe CITR aIIeIes among Caucasian
ouIalions roducing aImosl excIusiveIy (95%) exon 9-minus RNA. The effecl of lhis T-lracl
oIymorhism in CITR gene exression vas aIso documenled by ils reIalionshi vilh lhe
R117H mulalion: R117H (5T) is found in lyicaI CI alienls vilh ancrealic sufficiency,
R117H (7T) is associaled vilh CAVD. The R117H mulalion has been reorled in CI alienls,
maIes vilh congenilaI biIaleraI absence of lhe vas deferens, and in an asymlomalic voman.
Iurlhermore, ouIalion screening discovered a 19-foId higher lhan execled number of
carriers of lhis CI mulalion. The silualion vas comared lo lhal in Gaucher disease in vhich
lhe severily of neuronoalhic disease associaled vilh a missense mulalion aears lo be
aIlered by addilionaI missense mulalions in lhe same aIIeIe (Lalham el aI., 1990).
While el aI. (2001) reorled a heaIlhy 29-year-oId femaIe vho vas found lo be an
R117H/deII508 helerozygole. The alienl had aloic aslhma and inferliIily, bul normaI heighl
and veighl and no uImonary symloms of CI. AnaIysis of lhe oIylhymidine lracl shoved
lhal lhe R117H mulalion vas in cis vilh a 7T lracl and lhe deIla-I508 mulalion in cis vilh a 9T
lracl. The aulhors concIuded lhal oIy-T sludies are imorlanl in any alienl found lo have
lhe R117H mulalion, and recommended caulion in lhe genelic counseIing of such famiIies.
Thauvin-Robinel el aI. (2009) reorled lhe resuIls of a nalionaI coIIaboralive sludy in Irance lo
eslabIish lhe overaII henolye associaled vilh R117H and lo evaIuale lhe disease enelrance
of lhe R117H+I508deI genolye. In 184 R117H+I508deI individuaIs of lhe Irench ouIalion,
incIuding 72 nevborns, lhe disease henolye vas redominanlIy miId, 1 chiId had cIassic
cyslic fibrosis, and 3 aduIls had severe uImonary symloms. In 5,245 heaIlhy aduIls vilh no
famiIy hislory of CI, lhe aIIeIic revaIence of I508deI vas 1.06%, R117H,T7 0.27%, and
R117H,T5 Iess lhan 0.01%. The lheorelicaI number of R117H,T7+I508deI individuaIs in lhe
Irench ouIalions vas eslimaled al 3650, vhereas onIy 112 vere knovn vilh CI reIaled
symloms (3.1%). The enelrance of cIassic CI for R117H,T7+I508deI vas eslimaled al 0.03%
and lhal of severe CI in aduIlhood al 0.06%. Thauvin-Robinel el aI. (2009) suggesled lhal
R117H shouId be vilhdravn from CI mulalion aneIs used for screening rograms.
CITR, ARG347IRO |dbSNI:rs77932196j
In a famiIy idenlified as UT 1446, Dean el aI. (1990) found a C-lo-G lransversion al osilion
1172, resuIling in subslilulion of roIine for asarlic acid (R347I). The mulalion deslroyed an
HhaI reslriclion sile and crealed a NcoI sile.
CITR, ALA455GLU |dbSNI:rs74551128j
A C-lo-A change in nucIeolide 1496 in exon 9 Ieads lo subslilulion of gIulamic acid for aIanine
al osilion 455 (A455I) (Kerem el aI., 1990).
CITR, IVS10, G-A, -1 |dbSNI:rs76713772j
Kerem el aI. (1990) idenlified a sIice mulalion, a G-lo-A change of nucIeolide -1 in lhe
accelor sile of inlron 10. In a Irench alienl vilh cyslic fibrosis, GuiIIermil el aI. (1990)
delecled lhe same mulalion: a G-lo-A change in lhe Iasl nucIeolide al lhe 3-rime end of inlron
10 nucIeolide 1717 minus one. The mulalion deslroyed a sIice sile.
CITR, GLY542TIR |dbSNI:rs113993959j
A G-lo-T change in nucIeolide 1756 in exon 11 is resonsibIe for a slo mulalion in codon 542
(G542X) (Kerem el aI., 1990). Cuens el aI. (1990) found lhe same mulalion in a eIgian
alienl. The G542X mulalion accounled for 7.3% of lhe CI chromosomes in eIgium, being
robabIy lhe second mosl frequenl mulalion. (In a samIe of eIgian CI alienls, 68.1% of aII
CI chromosomes carried lhe deIla-I508 mulalion.) The cIinicaI manifeslalions vere miId in a
homozygole bul vere severe in a firsl cousin vho vas a genelic comound for G542X and
gIy458-lo-vaI (602421.0028). Lerer el aI. (1992) reorled lhal lhe gIy542-lo-ler mulalion
accounls for 13% of Ashkenazi CI mulalions.
CaslaIdo el aI. (1997) described severe Iiver invoIvemenl associaled vilh ancrealic
insufficiency and moderale uImonary exression of CI in a girI, homozygous for lhe G542X
mulalion, vho died al lhe age of 10 years.
Loiral el aI. (1997) suggesled lhal G542X is robabIy lhe Ihoenician cyslic fibrosis mulalion.
They shoved lhal lhe frequency of G542X varies among differenl lovns al regions of origin,
being Iover in norlheaslern Iuroeans lhan in soulhveslern Iuroeans. G542X mulalion
maing lhal lhey defined by muIliIe regression of G542X frequencies covered 28 counlries
(53 geograhic oinls) and vas based on dala from 50 Iaboralories. More eIevaled vaIues of
G542X frequency corresonded lo ancienl siles of occualion by occidenlaI Ihoenicians.
In a alienl vilh a severe form of cyslic fibrosis, Savov el aI. (1995) idenlified comound
helerozygosily for lhe G542X mulalion and an aIIeIe vilh a doubIe mulalion (S912L and
G1244V, 602421.0135).
CITR, SIR549ASN
A G-lo-A change in nucIeolide 1778 in exon 11 is resonsibIe for subslilulion of asaragine for
serine al osilion 549 (S549N) (Culling el aI., 1990).
CITR, SIR549ILI |dbSNI:rs121908755j
A G-lo-T change in nucIeolide 1778 in exon 11 is resonsibIe for subslilulion of isoIeucine for
serine al amino acid 549 (S549I) (Kerem el aI., 1990).
CITR, SIR549ARG |dbSNI:rs121908757j |dbSNI:rs121909005j
A T-lo-G change in nucIeolide 1779 in exon 11 is resonsibIe for subslilulion of arginine for
serine al amino acid 549 (S549R) (Kerem el aI., 1990). SangiuoIo el aI. (1991) found lhe same
ser549-lo-arg subslilulion in an IlaIian alienl vilh severe cyslic fibrosis, hovever, lhe
subslilulion vas caused by an A-lo-C change in nucIeolide 1777. Thus, lhe 2 mulalions are
AGT-lo-AGG and AGT-lo-CGT. A T-lo-C change al nucIeolide 1779 vouId aIso change serine
lo arginine.
Romey el aI. (1999) reorled a noveI comIex aIIeIe in lhe CITR gene, combining lhe S549R
mulalion due lo a T-lo-G lransversion in exon 11 vilh lhe firsl described sequence change in
lhe minimaI CITR romoler, a T-lo-A lransversion al osilion -102 (602421.0122). In a searale
ubIicalion, Romey el aI. (1999) comared lhe main cIinicaI fealures of 6 CI alienls carrying
lhe comIex aIIeIe vilh lhose of 16 CI alienls homozygous for lhe S549R mulalion aIone. Age
al diagnosis vas higher, and currenl age vas significanlIy higher (I 0.0032), in lhe grou
vilh lhe comIex aIIeIe, comared vilh lhe S549R/S549R grou. AIlhough lhe roorlion of
alienls vilh Iung coIonizalion vas simiIar in lhe 2 grous, lhe age al onsel vas significanlIy
higher in lhe grou vilh lhe comIex aIIeIe (I 0.0022). Ialienls vilh lhe comIex aIIeIe aIso
had significanlIy Iover sveal lesl chIoride vaIues (I 0.0028) and beller overaII cIinicaI scores
(I 0.004). None of lhe 22 alienls invoIved in lhis sludy had meconium iIeus. AII 16 alienls
homozygous for S549R, hovever, vere ancrealic insufficienl, as comared vilh 50% of
alienls carrying lhe comIex aIIeIe (I 0.013). Moreover, lhe singIe alienl homozygous for
lhe comIex aIIeIe resenled vilh miId disease al 34 years of age. These observalions slrongIy
suggesled lhal lhe sequence change in lhe CITR minimaI romoler allenuales lhe severe
cIinicaI henolye associaled vilh lhe S549R mulalion.
Romey el aI. (2000) osluIaled lhal lhe -102T-A sequence change may allenuale lhe effecls of
lhe severe S549R mulalion lhrough reguIalion of CITR exression. AnaIysis of lransienlIy
lransfecled ceII Iines vilh viIdlye and -102A varianl human CITR-direcled Iuciferase
reorler genes demonslraled lhal conslrucls conlaining lhe -102A varianl, vhich creales a Yin
Yang 1 (YY1) core eIemenl, increases CITR exression significanlIy. IIeclrohorelic mobiIily
shifl assays indicaled lhal lhe -102 sile is Iocaled vilhin a region of muIliIe DNA-rolein
inleraclions and lhal lhe -102A aIIeIe recruils secificaIIy an addilionaI nucIear rolein reIaled
lo YY1.
CITR, GLY551ASI |dbSNI:rs75527207j
A G-lo-A change in nucIeolide 1784 in exon 11 is resonsibIe for subslilulion of asarlic acid
for gIycine al amino acid 551 (G551D) (Culling el aI., 1990). Curlis el aI. (1991) described lhis
mulalion in 2 sibs in homozygous slale and in an unreIaled aduIl vho vas a comound
helerozygole for G551D and deIla-I507 (602421.0002). AII 3 shoved cIinicaIIy miId disease. The
G551D mulalion creales an MboI recognilion sile al codon 551 in lhe CITR gene. urger el aI.
(1991) suggesled lhal helerozygosily for lhe G551D mulalion is a causalive faclor in recurrenl
oIyosis nasi (nasaI oIys). Hamosh el aI. (1992) slaled lhal lhe gIy551-lo-as mulalion,
vhich is vilhin lhe firsl nucIeolide-binding foId of lhe CITR, is lhe lhird mosl common CI
mulalion, vilh a vorIdvide frequency of 3.1% among CI chromosomes. Regions vilh a high
frequency corresond lo areas vilh Iarge ouIalions of CeIlic descenl. To delermine vhelher
G551D confers a differenl henolye lhan does deIla-I508, Hamosh el aI. (1992) sludied 79
comound helerozygoles for lhe 2 mulalions in comarison vilh age- and sex-malched deIla-
I508 homozygoles from 9 CI cenlers in Iuroe and Norlh America. There vas Iess meconium
iIeus among lhe comound helerozygoles bul olhervise no slalislicaIIy significanl difference
vas found belveen lhe 2 grous. CIinicaI oulcome (afler survivaI of meconium iIeus) vas
indislinguishabIe.
DeIaney el aI. (1996) shoved lhal mice carrying lhe human G551D mulalion in lhe Cflr gene
shov cyslic fibrosis alhoIogy bul have a reduced risk of falaI inleslinaI bIockage comared
vilh 'nuII' mulanls, in keeing vilh lhe reduced incidence of meconium iIeus in G551D
alienls. The G551D mulanl mice shoved grealIy reduced CITR-reIaled chIoride lransorl,
disIaying aclivily (equivaIenl lo aroximaleIy 4% of viIdlye Cflr) inlermediale belveen
lhal of 'nuII' mice and Cflr inserlionaI mulanls vilh residuaI aclivily. The aulhors slaled lhal
Iong-lerm survivaI of lhese animaIs shouId rovide an exceIIenl modeI for lhe sludy of cyslic
fibrosis.
The G551D aIIeIe is associaled characlerislicaIIy vilh ouIalions of CeIlic descenl and is seen
al ils highesl revaIence in regions such as IreIand and rillany. Il is seen in diminishing
frequencies as one moves lo lhe soulhern and easlern orlions of Iuroe. An iniliaIIy uzzIing
henomenon vas lhe reIaliveIy high incidence of lhis mulalion in lhe Czech ReubIic (3.8%).
As oinled oul by obadiIIa el aI. (2002), hovever, ouIalion movemenls of lhe asl rovide
an exIanalion.
Accurso el aI. (2010) reorled lhe resuIls of a 2-hase cIinicaI lriaI using VX-770, a CITR
olenlialor, in 39 aduIls vilh cyslic fibrosis and al Ieasl 1 G551D aIIeIe. Sub|ecls received 150
mg of VX-770 every 12 hours for 28 days in hase 2 of lhe sludy. AII shoved a change in lhe
nasaI olenliaI difference from baseIine of -3.5 mV (range, -8.3 lo 0.5, I 0.02 for lhe vilhin-
sub|ecl comarison, I 0.13 vs Iacebo), and lhe median change in lhe IeveI of sveal chIoride
vas -59.5 mmoI er Iiler (range, -66.0 lo -19.0, I 0.008 vilhin-sub|ecl, I 0.02 vs Iacebo).
The median change from baseIine in lhe ercenl of redicled forced exiralory voIume in 1
second vas 8.7% (range, 2.3 lo 31.3, I 0.008 vilhin-sub|ecl, I 0.56 vs Iacebo). The VX-770
vas veII loIeraled. None of lhe sub|ecls vilhdrev from lhe sludy. AII severe adverse evenls
resoIved vilhoul lhe disconlinualion of VX-770.
CITR, ARG553TIR |dbSNI:rs74597325j
A C-lo-T change in nucIeolide 1789 in exon 11 is resonsibIe for a slo mulalion al amino acid
553 (R553X) (Culling el aI., 1990). aI el aI. (1991) described a alienl homozygous for lhe
arg553-lo-ler mulalion in exon 11. The alienl vas moderaleIy severeIy affecled. Hamosh el aI.
(1991) sludied a CI alienl vho vas a comound helerozygole for 2 nonsense mulalions,
R553X and W1316X (602421.0029). The alienl had undeleclabIe CITR mRNA in bronchiaI
and nasaI eilheIiaI ceIIs associaled vilh severe ancrealic disease bul unexecledIy miId
uImonary disease. The R553X mulalion has lhe fourlh highesl frequency vorIdvide, 1.5%,
according lo lhe CI Consorlium (Hamosh el aI., 1991). The alienl vas a 22-year-oId African
American femaIe, 1 of 2 alienls vilh miId uImonary disease reorled by Culling el aI.
(1990). CheadIe el aI. (1992) described a chiId vho desile being homozygous for lhe R553X
mulalion had onIy miId uImonary disease. They raised lhe ossibiIily lhal lhe Iack of CITR
rolein in airvay ceIIs may be Iess damaging lhan lhe resence of an aIlered rolein, a
suggeslion advanced by Culling el aI. (1990).
Chen el aI. (2005) reorled a Taivanese CI alienl vho vas homozygous for lhe R553X
mulalion. He had a severe cIinicaI course, vilh earIy onsel of chronic diarrhea, faiIure lo
lhrive, and frequenl resiralory infeclions. The arenls, vho vere nol reIaled, vere bolh
helerozygous for lhe mulalion. olh of lheir famiIies vere nalive lo Taivan, having been on
lhe isIand for al Ieasl 3 generalions. Chen el aI. (2005) noled lhal cyslic fibrosis is rare among
Asians and lhal homozygosily for R553X had onIy been reorled reviousIy in Caucasian
alienls.
Aznarez el aI. (2007) erformed lranscril anaIysis of 5 CI alienls vho vere comound
helerozygous for lhe R553X and deIla-I508 (602421.0001) mulalions. RT-ICR of alienl
IymhobIasloid ceIIs shoved variabIe IeveIs of an aberranlIy sIiced CITR isoform lhal
corresonded lo lhe skiing of exon 11. Use of a sIice reorler conslrucl indicaled lhal lhe
R553X subslilulion creales a ulalive exonic sIicing siIencer (ISS) lhal may resuIl in exon
skiing by revenling seIeclion of lhe roximaI 5-rime sIice sile. Ixon 11 skiing did nol
resuIl from a nonsense-associaled aIlered sIicing mechanism. Aznarez el aI. (2007) concIuded
lhal aminogIycoside lrealmenl vouId nol be effeclive for CI alienls vilh lhis mulalion
oving lo ils effecl of skiing exon 11.
CITR, ALA559THR |dbSNI:rs75549581j
A G-lo-A change in nucIeolide 1807 in exon 11 is resonsibIe for subslilulion of lhreonine for
aIanine al amino acid 559 (A559T) (Culling el aI., 1990).
CITR, ARG560THR |dbSNI:rs80055610j
A G-lo-C change in nucIeolide 1811 in exon 11 is resonsibIe for subslilulion of lhreonine for
arginine al amino acid 560 (R560T) (Kerem el aI., 1990).
CITR, TYR563ASN |dbSNI:rs121909006j
A T-lo-A change in nucIeolide 1819 in exon 12 is resonsibIe for subslilulion of asaragine for
lyrosine al amino acid 563 (Y563N) (Kerem el aI., 1990).
CITR, IRO574HIS |dbSNI:rs121908758j
A C-lo-A change in nucIeolide 1853 in exon 12 is resonsibIe for subslilulion of hislidine for
roIine al amino acid 574 (I574H) (Kerem el aI., 1990).
CITR, 2-I INS, 2566AT
Inserlion of 2 nucIeolides, AT, afler nucIeolide 2566 in exon 13 is resonsibIe for a frameshifl
(2566insAT) (While el aI., 1990).
CITR, 1-I DIL, 3659C
DeIelion of C al nucIeolide 3659 in exon 19 is resonsibIe for a frameshifl (3659deIC) (Kerem el
aI., 1990).
CITR, SIR1255TIR |dbSNI:rs76649725j
A C-lo-A change in nucIeolide 3896 in exon 20 is resonsibIe for a slo mulalion al amino acid
1255 (S1255X) (Culling el aI., 1990). This mulalion vas found in a bIack alienl vho inheriled
il from his falher. The chromosome inheriled from his molher carried anolher nonsense
mulalion, gIy542-lo-ler (602421.0009). The 11-year-oId boy had serious ancrealic disease bul
onIy miId uImonary invoIvemenl.
CITR, TRI1282TIR |dbSNI:rs77010898j
In a Irench alienl vilh cyslic fibrosis (219700), Vidaud el aI. (1990) idenlified lhe subslilulion
of lrylohan-1282 by a lerminalion codon. The olher chromosome carried lhe deIla-I508
mulalion. In anolher Irench alienl vilh cyslic fibrosis, Vidaud el aI. (1990) found reciseIy
lhe same mulalion on one chromosome bul lhe mulalion on lhe olher chromosome vas
unknovn. A G-lo-A subslilulion al nucIeolide 3978 vas resonsibIe for lhe lr1282-lo-ler
change. Hamosh el aI. (1991) ciled evidence lhal lhe W1282X mulalion, Iocaled in exon 20, is
lhe mosl common CI mulalion in lhe Ashkenazi }evish ouIalion vhere il is resenl on 50%
of CI chromosomes. In IsraeI, Shoshani el aI. (1992) found lhe W1282X mulalion in 63
chromosomes from 97 CI famiIies. Sixleen alienls homozygous for lhe W1282X mulalion and
22 alienls helerozygous for lhe deIla-I508 and W1282X mulalions had simiIarIy severe
disease, refIecled by ancrealic insufficiency, high incidence of meconium iIeus (37% and 27%,
resecliveIy), earIy age al diagnosis, oor nulrilionaI slalus, and variabIe uImonary funclion.
Again, lhe W1282X mulalion vas lhe mosl common form in Ashkenazi }evish alienls in
IsraeI. In lhe }evish Ashkenazi alienl ouIalion, 60% of lhe CI chromosomes carry lhe
W1282X nonsense mulalion. Ialienls homozygous for lhis mulalion have severe disease vilh
variabIe uImonary comIicalions. Sludies by Shoshani el aI. (1994) demonslraled lhal CITR
mRNA IeveIs in alienls homozygous for lhe W1282X mulalion are nol significanlIy decreased
by lhe mulalion. In alienls helerozygous for lhe mulalion, lhe reIalive IeveIs of mRNA vilh
lhe W1282X aIIeIe and eilher lhe deIla-I508 or lhe normaI aIIeIe vere simiIar in each alienl.
These resuIls indicaled lhal lhe severe cIinicaI henolye of alienls carrying lhe W1282X
mulalion is nol due lo a severe deficiency of mRNA. The severily, rogression, and variabiIily
of lhe uImonary disease aear lo be affecled by olher, as yel unknovn faclors.
.0023 CFTR POLYMORPHI5M
CITR, MIT470VAL |dbSNI:rs213950j
Kerem el aI. (1990) found 'normaI' A or G varialion al nucIeolide 1540 resuIling in melhionine
or vaIine, resecliveIy, al osilion 470.
CITR, ILI506VAL |dbSNI:rs1800091j
This mulalion vas found by Kobayashi el aI. (1990) in a comound helerozygole vilh deIla-
I508 (602421.0001). CIinicaI and eilheIiaI hysioIogic sludies yieIded normaI resuIls,
indicaling lhal lhe I506V mulalion is benign.
CITR, IHI508CYS |dbSNI:rs74571530j
This mulalion vas found by Kobayashi el aI. (1990) in a comound helerozygole vilh deIla-
I508 (602421.0001). CIinicaI and eilheIiaI hysioIogic sludies yieIded normaI resuIls,
indicaling lhal lhe I508C mulalion is benign.
CITR, TRI846TIR
In a Irench alienl vilh cyslic fibrosis, Vidaud el aI. (1990) found a reIacemenl of
lrylohan-846 by a slo codon on one chromosome, lhe nalure of lhe mulalion on lhe olher
chromosome vas unidenlified.
CITR, TYR913CYS |dbSNI:rs121909008j
In a Irench alienl vilh cyslic fibrosis, Vidaud el aI. (1990) idenlified subslilulion of lyrosine-
913 by cysleine. The olher chromosome carried lhe deIla-I508 mulalion. An A-lo-G
subslilulion al osilion 2870 vas resonsibIe for lhe lyr913-lo-cys change.
CITR, GLY458VAL |dbSNI:rs121909009j
Cuens el aI. (1990) described comound helerozygosily for lhe G542X mulalion
(602421.0009) and a change of gIycine-458 lo vaIine.
In a 21-year-oId bIack voman vilh subslanliaI ancrealic disease bul onIy miId uImonary
invoIvemenl, Culling el aI. (1990) found an A-lo-G subslilulion al nucIeolide 4079 in exon 21,
Ieading lo reIacemenl of lrylohan al codon 1316 by a lerminalion signaI. The mulalion
aeared lo have been inheriled from lhe falher, from lhe molher lhe alienl had inheriled lhe
arg553-lo-ler mulalion (602421.0014).
CITR, 2-I INS, 1154TC
Iannuzzi el aI. (1991) idenlified inserlion of 2 nucIeolides, T and C, al osilion 1154, redicling
a shifl in lhe reading frame of lhe rolein and lhe inlroduclion of a UAA(ochre) lerminalion
codon al residue 369. AIer el aI. (2003) described lhe lruncaled rolein as Iacking ATI
binding domains, lhe reguIalory domain, and lhe second lransmembrane domain and as
lhoughl lo be nonfunclionaI.
Screening 80 CITR alienls, AIer el aI. (2003) found lvo 1154insTC mulalions, bolh in
Caucasians, accounling for 1.25% of lhe CI chromosomes. They aIso reorled comound
helerozygosily vilh deII508 (602421.0001) in CI vilh ancrealic insufficiency and meconium
iIeus in a Caucasian maIe.
CITR, 1-I DIL, 1213T
In 2 sibs vilh cyslic fibrosis, Iannuzzi el aI. (1991) idenlified deIelion of lhymine al osilion
1213, vhich vas redicled lo shifl lhe reading frame of lhe rolein and lo inlroduce a
UAA(ochre) lerminalion codon al residue 368. The alienls had miIdIy imaired Iung
funclion.
CITR, ASN1303LYS |dbSNI:rs80034486j
Osborne el aI. (1991) reorled a C-lo-G change al nucIeolide 4041 resuIling in a change from
asaragine lo Iysine al amino acid osilion 1303 (N1303K). This mulalion vas found
excIusiveIy in helerozygous slale and no correIalion couId be made belveen cIinicaI
henolye and lhe resence of lhe gene. IooIing Iaboralories lhroughoul Iuroe and lhe
Uniled Slales, Osborne el aI. (1992) idenlified 216 examIes of N1303K among nearIy 15,000
CI chromosomes lesled, a frequency of 1.5%. The frequency vas grealer in soulhern lhan in
norlhern Iuroe, il vas nol found in U.K. Asians, American bIacks, or AuslraIians. Ten
alienls vere homozygous, vhereas 106 of lhe remainder carried 1 of 12 knovn CI mulalions
in lhe olher aIIeIe. Osborne el aI. (1992) concIuded lhal N1303K is a 'severe' mulalion vilh
resecl lo lhe ancreas, bul couId find no correIalion belveen lhis mulalion in eilher lhe
homozygous or helerozygous slale and lhe severily of Iung disease.
In a sludy of CI mulalions in soulh Iuroean cases, Gasarini el aI. (1991) found a nonsense
mulalion in exon 19 due lo a C-lo-T subslilulion al nucIeolide 3616. The normaI codon CGA,
vhich codes for arginine al osilion 1162, vas changed lo a slo codon UGA (R1162X). Il vas
delecled in 2 of 16 non-deIla-I508 chromosomes. In 9 alienls homozygous for lhis mulalion,
Gasarini el aI. (1992) found miId Iung disease. They had execled lhal lhe inlerrulion in lhe
synlhesis of lhe CITR rolein vouId resuIl in a severe cIinicaI course. The findings of miId lo
moderale invoIvemenl of lhe Iungs (aIlhough ancrealic insufficiency vas resenl in aII)
suggesled lo lhem lhal lhis form of lruncaled CITR rolein, sliII conlaining lhe reguIalory
region, lhe firsl ATI binding domain, and bolh lransmembrane domains, couId be arliaIIy
vorking in Iung lissues.
CITR, ARG334TRI |dbSNI:rs121909011j
In lhe course of a sludy of CI mulalions in soulh Iuroean cases, Gasarini el aI. (1991) found
a C-lo-T subslilulion al nucIeolide 1132 in exon 7. This oinl mulalion changed an arginine
codon lo a lrylohan al osilion 334 of lhe ulalive firsl lransmembrane domain of lhe
rolein (R334W). The alienl vas a comound helerozygole for mulalions R334X and N1303K
(602421.0032).
AnlinoIo el aI. (1997) comared lhe henolye of 12 alienls vilh cyslic fibrosis caused by lhe
R334W mulalion vilh lhose of homozygous deII508 alienls. Currenl age and age al
diagnosis vere significanlIy higher in lhe R334W mulalion grou. They found a Iover rale of
Iseudomonas aeruginosa coIonizalion in alienls carrying lhe R334W mulalion, aIlhough lhe
difference vas nol slalislicaIIy significanl. Hovever, lhey found a slalislicaIIy significanl
higher age of onsel of Iseudomonas aeruginosa coIonizalion in lhe grou of alienls vilh lhe
R334W mulalion. Iancrealic insufficiency vas found in a Iover ercenlage of R334W alienls
(33%). The body veighl exressed as a ercenlage of ideaI veighl for heighl vas significanlIy
higher in alienls vilh lhe R334W mulalion.
CITR, 2-I DIL, 1677TA |dbSNI:rs121908776j
In bolh arenls of a sibshi in vhich 3 chiIdren had died vilhin monlhs of birlh (2 vilh
neumonia and 1 vilh resumed meconium iIeus), Ivaschenko el aI. (1991) found lhe same
mulalion, nameIy, deIelion of 2 nucIeolides (TA) al osilion 1677. As a resuIl of lhe deIelion,
lhe rolein reading frame vas shifled, inlroducing a lerminalion codon (TAG) al amino acid
osilion 515 in lhe resuIling lranscril. The famiIy vas from a smaII Soviel elhnic grou caIIed
lhe MegraIs in veslern Georgia.
In a comound helerozygole vilh cyslic fibrosis, While el aI. (1991) found a de novo mulalion
vhich converled codon 851 (CGA,ARG) lo a slo codon (TGA). The molher Iacked any cyslic
fibrosis mulalion and lhe falher vas helerozygous for lhe common deIla-I508 mulalion.
CITR, GLY551SIR |dbSNI:rs121909013j
In 2 sislers vilh miId CI, lhe offsring of second-cousin arenls, Slrong el aI. (1991) found a
G-lo-A subslilulion al baseair 1783 resuIling in subslilulion of a serine for a gIycine residue al
lhe highIy conserved osilion of amino acid 551. The roosila vas a 50-year-oId voman vilh
a chronic roduclive cough. She had frequenl uImonary infeclions. Her sveal eIeclroIyle
concenlralions vere borderIine normaI. The alienl had 2 normaI regnancies and deIiveries
and raised lhese chiIdren vhiIe vorking as a lruck inseclor. The alienl had a sisler vho
died of resiralory faiIure al lhe age of 48. She had deIivered 4 heaIlhy chiIdren vilhoul
difficuIly, had no evidence of maIabsorlion, and vas in good heaIlh unliI lhe age of 23 vhen
she had an eisode of hemolysis. Al lhal lime she vas reorled lo have digilaI cIubbing and
bronchieclasis on chesl roenlgenograhy. SeveraI sveal lesls vere normaI.
CITR, GLY85GLU |dbSNI:rs75961395j
ChaIkIey and Harris (1991) found homozygosily for a G-lo-A mulalion al nucIeolide 386 in
exon 3 of lhe CITR gene, resuIling in subslilulion of gIulamic acid for gIycine-85. The alienl
vas an 11-year-oId boy of Iranian exlraclion in vhom lhe diagnosis of CI vas made vhen he
resenled vilh a nasaI oIy. He had sveal sodium vaIues of 90 mmoI er Iiler and miId Iung
disease and vas ancrealic sufficienl. The G85I mulalion vas firsl defined by ZieIenski el aI.
(1991) in a Irench-Canadian alienl vho vas a comound helerozygole.
In an IlaIian CI alienl knovn lo be a genelic comound, Ronchello el aI. (1992) found a C-lo-
T lransilion al nucIeolide 3604, vhich changed an arginine residue al osilion 1158 lo a slo
codon (R1158X). The alienl carried an unknovn mulalion on lhe olher chromosome and vas
ancrealic sufficienl.
CITR, IVS19, A-G, +4
In an IlaIian CI alienl vilh ancrealic insufficiency bul miId uImonary disease, Ronchello
el aI. (1992) found an A-lo-G lransilion Iocaled al lhe 5-rime end of inlron 19, vhich changed
lhe consensus sequence of lhe donor sile from GTGAGA lo GTGGGA (3849+4A-G).
CITR, 22-I DIL
As arl of a search for addilionaI CI mulalions, Dean el aI. (1992) used fIanking rimers for
exon 6A lo amIify DNA from over 150 CI alienls vho Iacked lhe deIla-I508 mulalion on al
Ieasl 1 chromosome. In 1 individuaI, a 22-b deIelion, beginning al nucIeolide 852 and
sloing 2 b before lhe end of lhe exon, vas found. The deIelion vas redicled lo aIler lhe
reading frame of lhe rolein, causing lhe inlroduclion of an in-frame lerminalion codon, TGA,
al amino acid 253. Dean el aI. (1992) slaled lhal vere no documenled cases of Iarge deIelions
and onIy 1 reorl of a de novo mulalion in lhe CITR gene.
CITR, 1-I DIL, 556A
ZieIenski el aI. (1991) idenlified an exon 4 mulalion lhal crealed a nev gII sile, a frameshifl
due lo deIelion of nucIeolide 556, an A.
CITR, 1-I DIL, 557T
In a alienl vilh cyslic fibrosis vilh reIaliveIy miId symloms, Graham el aI. (1992) idenlified
deIelion of a singIe nucIeolide, a T, in lhe T lracl from base 557 lo 561 in exon 4 of lhe CITR
gene. Like lhe 556A deIelion (602421.0042), lhe mulalion crealed a nev gII sile.
CITR, 84-I DIL, NT1949 |dbSNI:rs121908777j
y DNA amIificalion and direcl sequencing of 500 b of lhe 5-rime end of exon 13, GraneII
el aI. (1992) idenlified an 84-b deIelion in exon 13 of lhe CITR gene. The deIelion vas in lhe
malernaI aIIeIe of a CI alienl bearing lhe deIla-I508 deIelion in lhe falher's aIIeIe. The
deIelion sanned from a 4-A cIusler in osilions 1949-1952 lo anolher 4-A cIusler in osilions
2032-2035. The mulalion resuIled in lhe Ioss of 28 amino acid residues in lhe R domain of lhe
CITR rolein. Since lhis in-frame mulalion, lhe Iargesl idenlified lo lhal lime, began afler
nucIeolide 1949, il vas referred lo as 1949deI84. Oul of 340 Sanish CI alienls, Nunes el aI.
(1992) found 3 alienls vho vere comound helerozygoles for lhe 1949deI84 and deII508
mulalions and 1 for 1949deI84 and an unknovn mulalion. The alienls had a simiIar severily
of disease lo lhal in deII508 homozygous alienls.
CITR, 1-I INS, 2869G |dbSNI:rs121908788j
Nunes el aI. (1992) idenlified a frameshifl mulalion resuIling from inserlion of a guanine (G)
afler nucIeolide 2869 in exon 15. Direcl sequencing of a erson homozygous for lhis mulalion
shoved lhal il resuIled in a TGA slo codon al lhe sile of inserlion, foIIoved by anolher slo
signaI al lhe beginning of exon 16. The mulalion crealed a nev reslriclion sile for lhe MboI
endonucIease. Nunes el aI. (1992) demonslraled lhal lhe mulalion vas resenl in 6 of 191 non-
deII508 chromosomes in lhe Sanish ouIalion and in none of 86 IlaIian non-deII508
chromosomes. AII chromosomes carrying lhe mulalion had lhe same haIolye. A
homozygous alienl had a moderaleIy severe cIinicaI course. (This mulalion is aIso referred lo
as 2869insG.)
CITR, VAL520IHI |dbSNI:rs77646904j
In a alienl vilh CI, }ones el aI. (1992) used lhe chemicaI cIeavage mismalch lechnique lo
demonslrale a V520I mulalion vhich resuIled from a G-lo-T lransversion.
CITR, CYS524TIR |dbSNI:rs121908754j
Using lhe chemicaI cIeavage mismalch lechnique for lhe sludy of DNA from a alienl vilh CI,
}ones el aI. (1992) discovered a nonsense C524X mulalion resuIling from a C-lo-A lransversion.
CITR, GLN1291HIS |dbSNI:rs121909015j
Using lhe chemicaI cIeavage mismalch lechnique, }ones el aI. (1992) demonslraled a Q1291H
mulalion caused by a G-lo-C lransversion al lhe Iasl nucIeolide of exon 20. Iurlher sludy,
invoIving RNA-based ICR, demonslraled lhal lhe Q1291H is aIso a sIice mulalion. olh
correclIy and aberranlIy sIiced mRNAs vere roduced by lhe Q1291H aIIeIe. The incorreclIy
sIiced roducl resuIled from lhe use of a nearby crylic sIice sile 29 bases inlo lhe ad|acenl
inlron.
CITR, IHI311LIU |dbSNI:rs121909016j
Using DGGI in a syslemalic sludy in a CeIlic ouIalion in rillany, Ierec el aI. (1992)
idenlified a C-lo-G mulalion al nucIeolide 1065 changing codon 311 from henyIaIanine lo
Ieucine. The mulalion vas found in a comound helerozygole chiId vho vas cIassified as
ancrealic insufficienl, lhe olher aIIeIe vas gIy551-lo-as (602421.0013).
CITR, 2-I DIL, NT1221
In a syslemalic sludy of 365 CI chromosomes in lhe CeIlic ouIalion in rillany, Ierec el aI.
(1992) delecled a frameshifl mulalion in exon 7. The alienl, vho vas severeIy ancrealic
insufficienl, vas a comound helerozygole for a deIelion of 2 nucIeolides al osilion 1221. The
olher aIIeIe had a deIelion of T al 1078.
CITR, SIR492IHI |dbSNI:rs121909017j
(1992) idenlified a ser492-lo-he mulalion, due lo a change al nucIeolide 1607 from C lo T, in a
chiId cIassified as ancrealic sufficienl.
CITR, ARG560LYS |dbSNI:rs80055610j
(1992) idenlified an arg560-lo-Iys mulalion al lhe 3-rime end of exon 11, resuIling from a G-
lo-A lransilion al nucIeolide 1811. As veII as resuIling in an amino acid change in lhe rolein
roducl, lhe subslilulion in lhe Iasl residue of lhe exon may reresenl a sIice mulalion, a
simiIar change in exon 1 of lhe human bela-gIobin gene diminishes RNA sIicing (Vidaud el
aI., 1989, see hemogIobin Kairouan, H, ARG30THR, 141900.0144). The alienl vas
ancrealic insufficienl.
CITR, GLU827TIR |dbSNI:rs121909018j
In a chiId vilh ancrealic insufficienl cyslic fibrosis in lhe CeIlic ouIalion of rillany, Ierec
el aI. (1992) idenlified a G-lo-T change al osilion 2611 in exon 13 Ieading lo change of
gIulamic acid-827 lo a slo codon.
In a ancrealic insufficienl alienl in lhe CeIlic ouIalion of rillany, Ierec el aI. (1992) found
an arg1066-lo-his mulalion resuIling from a G-lo-A lransilion al nucIeolide 3329. This CG
dinucIeolide is a knovn holsol for mulalions. Ierec el aI. (1992) quoled unubIished resuIls
indicaling lhal anolher mulalion, C3328 lo T Ieading lo arg1066-lo-cys, had been discovered
(602421.0058). The chiId vilh lhe arg1066-lo-his mulalion vas a comound helerozygole, lhe
olher aIIeIe having a deIelion of T al nucIeolide 1078.
CITR, ALA1067THR |dbSNI:rs121909020j
In a ancrealic insufficienl chiId in lhe CeIlic ouIalion in rillany, Ierec el aI. (1992) found a
G-lo-A lransilion al osilion 3331 resuIling in an aIa1067-lo-lhr subslilulion. The modificalion
reIaced a nonoIar residue vilh a oIar residue. The olher chromosome carried lhe deIla-
I508 mulalion (602421.0001).
CITR, IVS20, G-A, +1
In a ancrealic insufficienl alienl in lhe CeIlic ouIalion of rillany, Ierec el aI. (1992)
idenlified a G-lo-A mulalion in lhe firsl nucIeolide of lhe sIice donor sile of inlron 20.
CITR, 5-I DUI, NT3320
In a ancrealic insufficienl alienl in lhe CeIlic ouIalion of rillany, Ierec el aI. (1992) found
duIicalion of 5 nucIeolides (CTATG) afler nucIeolide 3320, crealing a frameshifl.
CITR, ARG1066CYS |dbSNI:rs78194216j
Ierec el aI. (1992) ciled unubIished resuIls of I. Ianen: a C-lo-T lransilion al nucIeolide 3328
Ied lo an arg1066-lo-cys subslilulion. This CG dinucIeolide is a holsol for mulalions, see
602421.0054.
CITR, 1-I DIL, 1078T |dbSNI:rs121908744j
See 602421.0050. CIauslres el aI. (1992) found lhis mulalion in exon 7 in a CI alienl from
soulhern Irance. Romey el aI. (1993) described an imroved rocedure lhal aIIovs lhe
deleclion of singIe baseair deIelions on nondenaluring oIyacryIamide geIs and
demonslraled ils aIicabiIily for idenlifying lhis mulalion.
.0060 VA5 DEFEREN5, CONGENITAL BILATERAL AB5ENCE OF
CITR, ASI1270ASN |dbSNI:rs11971167j
In a sludy of 25 unreIaled, unseIecled vhile azoosermic men vilh cIinicaIIy diagnosed
congenilaI biIaleraI absence of lhe vas deferens (CAVD), aged 24 lo 43 years, Anguiano el aI.
(1992) found 2 in vhom lhere vas helerozygosily for lhe he508-lo-deI mulalion (602421.0001)
vilh anolher rare mulalion on lhe olher chromosome. In 1 alienl, of IngIish/IlaIian
exlraclion, lhe second mulalion vas a G-lo-A lransilion resuIling in subslilulion of asaragine
for asarlic acid al amino acid 1270 (D1270N). The alienl had a normaI chesl x-ray and sveal
eIeclroIyles veII vilhin lhe normaI range. There vere no signs of uImonary or
gaslroinleslinaI disease and no signs of overl maIabsorlion. Thus, lhe alienl had a rimariIy
genilaI form of cyslic fibrosis. olh lhis mulalion and lhe G576A mulalion (602421.0061) occur
vilhin lhe adenosine lrihoshale-binding domains of lhe CITR rolein. These domains are
beIieved lo Iay a roIe in lhe reguIalion of chIoride lransorl. Il is ossibIe lhal lhe ceIIs of lhe
deveIoing voIffian ducl have reguIalory alhvays funclionaIIy associaled lo CITR lhal are
differenl from lhe Iung, ancreas, or sveal ducl.
CITR, GLY576ALA |dbSNI:rs1800098j
In a man vilh isoIaled congenilaI biIaleraI absence of lhe vas deferens and vilh none of lhe
olher manifeslalions associaled vilh cyslic fibrosis, Anguiano el aI. (1992) found comound
helerozygosily for lhe he508-lo-deI (602421.0001) mulalion and anolher rare mulalion: a
GGA-lo-GCA lransversion in codon 576 in exon 12, redicled lo cause a subslilulion of aIanine
for gIycine.
CITR, 3849+10K, C-T |dbSNI:rs75039782j
AbeIiovich el aI. (1992) found lhal among 94 Ashkenazi }evish alienls vilh CI in IsraeI, 5
mulalions accounled for 97% of mulanl CITR aIIeIes. Iour of lhese vere deII508
(602421.0001), G542X (602421.0009), W1282X (602421.0022), and N1303K (602421.0032). The
fiflh, vhich accounled for 4% of aIIeIes, vas an unusuaI mulalion found by Highsmilh (1991).
Referred lo as 3849+10kbC-T, il vas delecled by cIeavage of a ICR roducl by HhI.
Highsmilh el aI. (1991) delecled lhe 3849+10kbC-T mulalion in a 19-year-oId Iakislani voman
vilh miId manifeslalions of CI and normaI sveal chIoride vaIues. To exIain lhe miIder
course of lhe disease in alienls vilh lhis mulalion, Highsmilh el aI. (1991) hyolhesized lhal
lhe C-lo-T base subslilulion crealed an aIlernalive sIice sile, vhich resuIled in inserlion of 84
baseairs inlo lhe CITR coding region. This change may cause synlhesis of a rolein vilh
normaI CITR funclion logelher vilh a nonfunclionaI rolein. AIlernaliveIy, lhis mulalion
mighl Iead lo roduclion of a rolein lhal is onIy arlIy funclionaI and causes miIder disease.
In IsraeI, Augarlen el aI. (1993) invesligaled 15 alienls vilh CI and lhis mulalion, aII
Ashkenazi }evs. Their cIinicaI fealures vere comared vilh lhose of CI alienls vilh
mulalions knovn lo be associaled vilh severe disease. Ialienls vilh lhe 3849+10kbC-T
mulalion vere oIder, had been diagnosed as having CI al a more advanced age, and vere in a
beller nulrilionaI slale. Sveal chIoride vaIues vere normaI in 5 of lhe 15 alienls, 4 of lhese
alienls and 6 olhers had normaI ancrealic funclion. Hovever, age-ad|usled uImonary
funclion did nol differ belveen lhese alienls and lhose vilh mulalions knovn lo cause
severe disease. None of lhe alienls vilh lhe 3849+10kbC-T mulalion had had meconium iIeus
and none had Iiver disease or diabeles meIIilus.
CITR, ARG1283MIT |dbSNI:rs77902683j
CheadIe el aI. (1992) idenlified a nev CITR mulalion vhich, Iike lhe lr1282-lo-ler mulalion
(602421.0022), aboIishes an MnIII reslriclion sile. The nev mulalion vas found lo be a G-lo-T
lransversion al osilion 3980 resuIling in reIacemenl of arginine by melhionine al residue
1283.
Slrong el aI. (1992) used chemicaI mismalch cIeavage and subsequenl DNA sequencing lo
idenlify a sIice mulalion al lhe 5-rime end of inlron 12 of lhe CITR gene. A G-lo-A
lransilion al osilion 1 of lhe donor-sIice sile resuIled in skiing of exon 12. The mulalion
vas found in comound helerozygous slale vilh lhe deII508 mulalion in a 39-year-oId vhile
maIe and a 9-year-oId femaIe vilh lyicaI uImonary and gaslroinleslinaI changes of CI. olh
vere ancrealic insufficienl. The maIe had a hislory of Iiver disease requiring sIenorenaI
shunl for orlaI hyerlension al age 14 years.
CITR, GLN359LYS AND THR360LYS |dbSNI:rs75053309j
Shoshani el aI. (1993) found lhal 88% of idenlified CI chromosomes among CI alienls vho
vere }evs from Soviel Georgia had a doubIe mulalion in ad|acenl codons: one aIleralion vas a
C-lo-A lransversion al nucIeolide osilion 1207, changing lhe gIulamine codon lo Iysine
(Q359K), lhe second aIleralion vas a C-lo-A lransversion al nucIeolide osilion 1211, changing
lhe lhreonine codon lo Iysine (T360K).
CITR, IVS6, 12-I DIL
In a ancrealic-insufficienl CI alienl, Audrezel el aI. (1993) found comound helerozygosily
for a deIla-I508 mulalion and a noveI mulalion vhich lhey designaled 876--14 deI 12 NT: a
Iarge deIelion vhich began al osilion -14 of exon 6b corresonded lo a Ioss of 12 nucIeolides.
ecause lhe mulalion invoIved a 4-b reeal (GATT), lhe deIelion couId invoIve 8 nucIeolides
deending on lhe aIIeIe in vhich il occurred.
CITR, ARG347LIU |dbSNI:rs77932196j
In a 2-year-oId girI delecled during a syslemalic neonalaI screening vho vas u lo lhal lime
symlom free and ancrealic sufficienl, Audrezel el aI. (1993) found a G-lo-T lransversion al
b 1172 changing arginine (an amino acid vilh a basic side chain) lo Ieucine (bearing a
nonoIar side chain) al residue 347. Audrezel el aI. (1993) oinled oul lhal 2 olher mulalions
invoIving nucIeolide 1172 have been observed, one Ieading lo R347I (602421.0006) and lhe
olher lo R347H (602421.0078). olh are associaled vilh ancrealic sufficiency.
CITR, ALA349VAL |dbSNI:rs121909021j
In lhe course of screening lhe normaI husband of a helerozygous voman, Audrezel el aI.
(1993) found a C-lo-T lransilion al nucIeolide 1178 redicling subslilulion of vaIine for aIanine
al residue 349. Since bolh of lhese amino acids carry a nonoIar side chain, il vas nol obvious
lhal lhe varialion vouId Iead lo a CI aIIeIe. Hovever, lhis nucIeolide change vas nol observed
on more lhan 300 normaI chromosomes screened, and aIanine al osilion 349 is conserved in
lhe CITR gene of human, Xenous, and cov.
Audrezel el aI. (1993) observed a C-lo-T lransilion al nucIeolide 1733 Ieading lo subslilulion of
gIulamic acid for aIanine-554. The change is a draslic one since il reIaces an acidic residue
vilh one vhich is nonoIar. Observed in helerozygoles, lhe mulalion is robabIy of funclionaI
significance.
CITR, LYS716TIR |dbSNI:rs121909023j
Audrezel el aI. (1993) found an A-lo-T lransversion al nucIeolide 2278 resuIling in a slo
codon al Iysine-716. The mulalion vas delecled in lhe helerozygous falher of a deceased chiId,
no cIinicaI dala vere avaiIabIe.
In a 2-year-oId chiId vho carried lhe deIla-I508 mulalion and manifesled cIassic symloms of
CI, nameIy, ancrealic insufficiency and uImonary disease, Audrezel el aI. (1993) delecled
on lhe olher chromosome a G-lo-A lransilion in lhe firsl nucIeolide in lhe 5-rime sIice sile of
inlron 13. Audrezel el aI. (1993) referred lo lhis mulalion as foIIovs: 2622 +1 G-lo-A.
In a alienl vilh cIassic ancrealic-insufficienl CI, Audrezel el aI. (1993) found a C-lo-T
lransilion al nucIeolide 3844 crealing a slo codon (TAG) in Iace of gIulamine (CAG). The
olher chromosome carried lhe G542X mulalion (602421.0009).
CITR, IVS19, G-A, -1
In 3 chiIdren vilh cIassic cyslic fibrosis, aII vilh ancrealic insufficiency, Audrezel el aI. (1993)
observed a G-lo-A lransilion al nucIeolide -1 of inlron 19, invoIving lhe sIice accelor sile
(3850, -1, G-lo-A).
CITR, 1-I INS, 3898C
In a severeIy affecled, ancrealic insufficienl, 20-year-oId alienl vilh cyslic fibrosis, Audrezel
el aI. (1993) found inserlion of a C afler nucIeolide 3898 resuIling in frameshifl. The olher
chromosome carried lhe R1162X mulalion (602421.0033).
In 2 alienls vilh ancrealic-insufficienl cyslic fibrosis, Audrezel el aI. (1993) found
comound helerozygosily for a G-lo-A lransilion al nucIeolide 302 in exon 3 converling codon
57 from TGG (lr) lo TGA (slo).
In a severeIy affecled, ancrealic-insufficienl alienl vilh cyslic fibrosis, Audrezel el aI. (1993)
found homozygosily for a C-lo-T lransilion al nucIeolide 4069 in exon 21 converling gIn1313 lo
a slo codon.
CITR, GLU92LYS
In a Sanish alienl vilh miId cyslic fibrosis, Nunes el aI. (1993) found a G-lo-A lransilion al
nucIeolide 406 resuIling in a change of codon 92 in exon 4 from gIulamic acid lo Iysine. The
same mulalion vas found in homozygous slale in a Turkish alienl vilh consanguineous
arenls Iiving in Germany. olh alienls vere ancrealic sufficienl and had normaI fal
excrelion. In bolh cases hysicaI aclivily Ied raidIy lo excessive svealing and faligue, lhe
molher of lhe Turkish boy reorled lhal afler 1 hour of sorls lhe boy's skin and hair became
covered vilh a vhile saIly crusl vhich required 2 or 3 shovers lo remove.
Audrezel el aI. (1993) referred lo an R347H mulalion causing ancrealic-sufficienl fibrosis.
This is 1 of 3 mulalions lhal invoIve nucIeolide 1172, lhe olhers being R347I (602421.0006) and
R347L (602421.0067).
CITR, GLY91ARG |dbSNI:rs121908750j
In a sludy of 87 non-deII508 chromosomes of relon origin, GuiIIermil el aI. (1993) found a
G91R mulalion. Three affecled ersons vho vere comound helerozygole for lhis and lhe
deII508 mulalion vere ancrealic sufficienl.
CITR, IHI1286SIR |dbSNI:rs121909028j
Using denaluring geI eIeclrohoresis foIIoved by direcl sequencing of lhe ICR roducls,
DorvaI el aI. (1993) found an I1286S mulalion in exon 20 of lhe CITR gene. A T-lo-C lransilion
al nucIeolide 3989 vas resonsibIe for lhe change from henyIaIanine lo serine.
CITR, 1-I INS, 2307A |dbSNI:rs121908787j
y chemicaI mismalch cIeavage in an African American alienl vilh cyslic fibrosis, Smil el aI.
(1993) found homozygosily for inserlion of an adenine afler nucIeolide 2307 in exon 13. The
resuIling shifl of lhe reading frame al codon 726 inlroduced 2 conseculive slo codons al
amino acid osilions 729 and 730. To examine lhe mRNA IeveI associaled vilh lhe 2307insA
mulalion, RNA from nasaI eilheIiaI ceIIs of lhe alienl and a normaI sub|ecl vere reverse
lranscribed. Subsequenl amIificalion of lhe cDNA demonslraled lhal lhe CITR message IeveI
associaled vilh 2307insA vas markedIy reduced comared lo lhe normaI conlroI, vhiIe bolh
lhe alienl and lhe normaI sub|ecl shoved simiIar IeveIs of exression.
In each of 4 German alienls vilh cyslic fibrosis, WiII el aI. (1994) found a G-lo-T lransversion
lhal affecled lhe firsl base of exon 4 and crealed a lerminalion codon gIu92-lo-ler. Lymhocyle
RNA of alienls helerozygous for lhe I92X mulalion vere found lo conlain lhe viIdlye
sequence and a differenliaIIy sIiced isoform Iacking exon 4. On lhe olher hand, RNA derived
from nasaI eilheIiaI ceIIs of lhese alienls shoved a lhird fragmenl of Ionger Ienglh.
Sequencing reveaIed lhe resence of I92X and an addilionaI 183-b fragmenl, inserled
belveen exons 3 and 4. The 183-b sequence vas maed lo inlron 3 of lhe CITR gene. Il vas
fIanked by accelor and donor sIice siles. WiII el aI. (1994) concIuded lhal lhe 183-b
fragmenl in inlron 3 is a crylic CITR exon lhal can be aclivaled in eilheIiaI ceIIs by lhe
resence of lhe I92X mulalion. I92X aboIishes correclIy sIiced CITR mRNA and Ieads lo
severe cyslic fibrosis.
CITR, GLY480CYS |dbSNI:rs79282516j
In a ancrealic insufficienl, African American CI alienl, Smil el aI. (1995) found a noveI
CITR missense mulalion associaled vilh a rolein lrafficking defecl in mammaIian ceIIs bul
normaI chIoride channeI roerlies in a Xenous oocyle assay. The mulalion resuIled in
subslilulion of a cysleine for gIycine al residue 480. In mammaIian ceIIs, lhe encoded mulanl
rolein vas nol fuIIy gIycosyIaled and faiIed lo reach lhe Iasma membrane, suggesling lhal
lhe G480C rolein vas sub|ecl lo defeclive inlraceIIuIar rocessing. Hovever, in Xenous
oocyles, a syslem in vhich mulanl CITR roleins are Iess IikeIy lo exerience an inlraceIIuIar
rocessing/lrafficking deficil, exression of G480C CITR vas associaled vilh a chIoride
conduclance lhal exhibiled a sensilivily lo aclivalion by forskoIin and 3-isobulyI-1-
melhyIxanlhine (IMX) lhal vas simiIar lo lhal of viIdlye CITR. This aeared lo be lhe firsl
idenlificalion of a CITR mulanl in vhich lhe soIe basis for disease vas misIocalion of lhe
rolein.
CITR, LIU206TRI |dbSNI:rs121908752j
The Ieu206-lo-lr (L206W) mulalion of lhe CITR gene vas firsl idenlified in 3 CI alienls
from Soulh Irance (CIauslres el aI., 1993). Rozen el aI. (1995) reorled lhal il is reIaliveIy
frequenl in Irench Canadians from Quebec. On lhe basis of findings in 7 Irench-Canadian
robands, lhey suggesled lhal lhis mulalion is IikeIy lo be resenl in alienls vilh alyicaI
forms of CI and may be resenl in olhervise heaIlhy men and vomen vilh inferliIily. Their
grou conlained 47-year-oId and 48-year-oId sislers and lheir 30-year-oId brolher. The vomen
vere lhoughl lo have reduced ferliIily and lhe man had absence of lhe vas deferenlia. The man
and 1 sisler had normaI uImonary funclion and high-resoIulion CT scan of lhe chesl. The 47-
year-oId sisler had had Iefl uer Iobeclomy for resumed bronchieclasis al lhe age of 20 years
and had had frequenl uImonary infeclions bul had surrisingIy veII-reserved Iung
funclion.
CIain el aI. (2005) noled lhal lhe L206W mulalion can resuIl in variabIe disease henolyes.
IndividuaIs bearing lhis mulalion in lrans vilh lhe severe CI-causing mulalion I508deI
(602421.0001) may have CI or isoIaled congenilaI biIaleraI absence of lhe vas deferens
(277180). CIain el aI. (2005) sludied lhe effecl of lhe L206W mulalion on CITR rolein
roduclion and funclion and examined lhe genolye-henolye correIalion of L206W/I508deI
comound helerozygole alienls. They shoved lhal L206W is a rocessing (cIass II) mulalion,
as lhe CITR biosynlhelic alhvay vas severeIy imaired, vhereas singIe-channeI
measuremenls indicaled ion conduclance simiIar lo lhe viIdlye rolein. These dala raised
lhe Iarger queslion of lhe henolyic variabiIily of cIass II mulanls, incIuding I508deI. CIain el
aI. (2005) concIuded lhal since muIliIe olenliaI roerlies couId modify lhe rocessing of lhe
CITR rolein during ils course lo lhe ceII surface, environmenlaI and olher genelic faclors
mighl conlribule lo lhis variabiIily.
urger el aI. (1991) suggesled lhal helerozygosily for lhe G551D mulalion (602421.0013) is a
causalive faclor in recurrenl nasaI oIys. Iresenlalion vilh a nasaI oIy vas lhe basis of lhe
diagnosis of cyslic fibrosis in an 11-year-oId boy of Iranian exlraclion in vhom ChaIkIey and
Harris (1991) found homozygosily for a gIy85-lo-gIu mulalion (602421.0038). Varon el aI.
(1995) described recurrenl nasaI oIys as a monosymlomalic form of cyslic fibrosis in
associalion vilh a noveI in-frame mulalion, deIelion of 18 b in exon 4 of lhe CITR gene. Since
lhe deIelion slarled vilh nucIeolide 591 of lheir cDNA cIone, lhe mulalion vas symboIized
591deI18. Il vas found in maIe lvins of Turkish origin. The lvins inheriled lhe 591deI18
mulalion from lheir molher. On lhe alernaI aIIeIe, lhey carried lhe nonsense mulalion gIu831-
lo-ler (VerIingue el aI., 1994). The alienls had been diagnosed as having CI al lhe age of 10
years due lo ersislenl nasaI oIys and eIevaled sveal eIeclroIyles. NasaI oIys had been
surgicaIIy removed on 4 occasions. The neonalaI eriod and earIy infancy vere comIeleIy
unevenlfuI. They vere ancrealic sufficienl and had no Iung disease or olher CI-reIaled
robIems.
RONCHIICTASIS WITH OR WITHOUT ILIVATID SWIAT CHLORIDI 1, MODIIIIR OI
CITR, IVS8AS, 5T VARIANT
ZieIenski el aI. (1995) eslimaled lhal CAVD is associaled vilh lhe 5T varianl al lhe 3-rime
end of inlron 8 of lhe CITR gene vilh a enelrance of 0.60 in maIes. Chu el aI. (1993) noled
varied Ienglhs of a lhymidine (T)-lracl (5, 7, or 9T) in fronl of lhe sIice-accelor sile of inlron
8. The Ienglh aeared lo correIale vilh lhe efficiency of exon 9 sIicing, vilh lhe 5T varianl
lhal is resenl in 5% of lhe CITR aIIeIes among lhe Caucasian ouIalion roducing aImosl
excIusiveIy (95%) exon 9-minus mRNA. The effecl of lhis T-lracl oIymorhism in CITR gene
exression vas aIso documenled by ils reIalionshi vilh lhe CI mulalion R117H
(602421.0005): vhiIe R117H (5T) is found in lyicaI CI alienls vilh ancrealic sufficiency,
R117H (7T) is associaled vilh CAVD (Kieseveller el aI., 1993).
Cosles el aI. (1995) sludied lhe CITR gene in 45 azoosermic individuaIs vilh isoIaled
CAVD. They delecled a CITR gene defecl in 86% of chromosomes from lhese sub|ecls. In
addilion lo idenlifying 9 noveI CITR gene mulalions, lhey found lhal 84% of men vilh
CAVD vho vere helerozygous for a CI mulalion carried lhe inlron 8 oIyyrimidine 5T
CITR aIIeIe on 1 chromosome.
De Meeus el aI. (1998) found Iinkage disequiIibrium belveen lhe 5T aIIeIe and lhe vaI aIIeIe of
lhe mel470-lo-vaI oIymorhism (602421.0023).
Groman el aI. (2004) demonslraled lhal lhe number of TG reeals ad|acenl lo 5T infIuences
disease enelrance. They delermined TG reeal number in 98 alienls vilh maIe inferliIily
due lo congenilaI absence of lhe vas deferens, 9 alienls vilh noncIassic CI, and 27 unaffecled
individuaIs (ferliIe men). Iach of lhe individuaIs in lhis sludy had a severe CITR mulalion on
one CITR gene and 5T on lhe olher. They found lhal lhose individuaIs vilh 5T ad|acenl lo
eilher 12 or 13 TG reeals vere subslanliaIIy more IikeIy lo exhibil an abnormaI henolye
lhan lhose vilh 5T ad|acenl lo 11 TG reeals. Thus, delerminalion of TG reeal number viII
aIIovs for more accurale rediclion of benign versus alhogenic 5T aIIeIes.
The TG reeal Iocaled al lhe sIice accelor sile of exon 9 of lhe CITR gene is an examIe of a
variabIe dinucIeolide reeal lhal affecls sIicing. Higher reeal numbers resuIl in reduced
exon 9 sIicing efficiency and, in some inslances, lhe reduclion in fuII-Ienglh lranscril is
sufficienl lo cause maIe inferliIily due lo congenilaI biIaleraI absence of lhe vas deferens or
noncIassic cyslic fibrosis. Using a CITR minigene syslem, Hefferon el aI. (2004) sludied TG
lracl varialion and observed lhe same correIalion belveen dinucIeolide reeal number and
exon 9 sIicing efficiency seen in vivo. ReIacemenl of lhe TG dinucIeolide lracl in lhe
minigene vilh random sequence aboIished sIicing of exon 9. ReIacemenls of lhe TG lracl
vilh sequences lhal can seIf-baseair suggesled lhal lhe formalion of an RNA secondary
slruclure vas associaled vilh efficienl sIicing. Hovever, sIicing efficiency vas inverseIy
correIaled vilh lhe redicled lhermodynamic slabiIily of such slruclures, demonslraling lhal
inlermediale slabiIily vas olimaI. IinaIIy, subslilulion of TA reeals of differing Ienglhs
confirmed lhal slabiIily of lhe RNA secondary slruclure, nol sequence conlenl, correIaled vilh
sIicing efficiency. Taken logelher, lhese dala indicaled lhal dinucIeolide reeals can form
secondary slruclures lhal have variabIe effecls on RNA sIicing efficiency and cIinicaI
henolye.
In a 66-year-oId voman and an unreIaled 67-year-oId man vilh idioalhic bronchieclasis
(ISC1, 211400), vho vere helerozygous for lhe 5T CITR varianl, Ia|ac el aI. (2008) aIso
idenlified helerozygosily for a missense mulalion in lhe SCNN1 gene (600760.0015). The
voman had a borderIine eIevaled sveal chIoride, normaI nasaI olenliaI difference (ID), and
IIV1 lhal vas 77% of redicled. The man had normaI sveal chIoride and nasaI ID, and IIV1
lhal vas 80% of redicled. Ia|ac el aI. (2008) concIuded lhal varianls in SCNN1 may be
deIelerious for sodium channeI funclion and Iead lo bronchieclasis, eseciaIIy in alienls vho
CITR, THR338ILI |dbSNI:rs77409459j
In aII 8 chiIdren of Sardinian descenl seen because of hyolonic dehydralion associaled vilh
hyonalremia, hyochIoremia, hyokaIemia, and melaboIic aIkaIosis, Leoni el aI. (1995) found
a T338I mulalion eilher in homozygosily or comound helerozygosily vilh anolher CI
mulalion. None had uImonary or ancrealic invoIvemenl. The T338I mulalion vas nol
delecled in alienls vilh CI vho had cIassic symloms or in heaIlhy ersons of lhe same
descenl. Their dala suggesled lhal lhe T338I mulalion is associaled vilh a secific miId cyslic
fibrosis henolye. The alienls vere seen al ages varying belveen 2 monlhs and 7 years of
age. Three of lhe alienls had faiIed lo lhrive. The sveal chIoride concenlralion vas high in aII
alienls bul 1, vho al 3 monlhs of age had borderIine vaIues. AII lhe alienls had normaI
slealocril vaIues for lheir age, and none of lhem required ancrealic enzyme suIemenls.
Shoshani el aI. (1994) idenlified a G-lo-A lransilion al nucIeolide 3398 of exon 17b of lhe CITR
gene in 2 of 138 aIIeIes in }evish alienls. This subslilulion resuIls in a lerminalion codon
(TAG) inslead of lrylohan al residue 1089. olh mulanl chromosomes carry lhe same exlra-
and inlragenic haIolye, A112.
y direcl sequencing of exon 21, Shoshani el aI. (1994) reveaIed a 4-b deIelion, TATT, al
osilion 4010 of lhe coding sequence. This frameshifl mulalion is execled lo creale a
lerminalion codon (TAG) 34 amino acids dovnslream of lhe mulalion. This aIleralion is IikeIy
lo be a disease-causing mulalion since il is redicled lo creale a lruncaled oIyelide lhal
Iacks lhe second ATI binding domain. The alienl is of Arab origin and inheriled lhis deIelion
from her falher. The CITR chromosome carries lhe D121 haIolye. Her olher CITR
chromosome has lhe asn1303-lo-Iys mulalion (602421.0032).
In a sludy of 224 non-I508deI CI chromosomes, Ghanem el aI. (1994) idenlified a C-lo-T
subslilulion al nucIeolide 223, changing arginine lo cysleine al osilion 31, in a Irench couIe
vilh cyslic fibrosis and one affecled chiId. Since lheir aarenlIy unaffecled 6-year-oId chiId
vas found lo be homozygous for lhis mulalion, il is robabIy a oIymorhism. The falher and
lhe affecled chiId had anolher subslilulion changing an isoIeucine-556 lo vaIine in exon 11.
This mulalion can be delecled by reslriclion anaIysis since il aboIishes a HhaI recognilion
sequence.
CITR, TYR109CYS |dbSNI:rs121909031j
SchaedeI el aI. (1994) idenlified an A-lo-G subslilulion al nucIeolide 458 in exon 4, converling
lyrosine-109 lo cysleine. The alienl is a 16-year-oId girI vilh CI (diagnosed al age 9 monlhs)
vho has remained ancrealic sufficienl. Her second mulalion vas 3659deIC (602421.0020) in
exon 19. The 3659deIC mulalion is associaled vilh lhe ancrealic insufficiency henolye. The
aulhors concIuded lhal lyr109-lo-cys is lhe mulalion conferring ancrealic sufficiency.
CITR, ARG352GLN |dbSNI:rs121908753j
In a syslemalic sludy of 133 CI individuaIs in norlhern IlaIy, Gasarini el aI. (1993) idenlified
an arg352-lo-gIu mulalion.
CITR, IVS3, A-G, +4
Ghanem el aI. (1994) idenlified an A-lo-G subslilulion al lhe fourlh nucIeolide of lhe donor
sIice sile of inlron 3. Il is nol knovn if lhis mulalion is draslic enough lo cause aberranl
sIicing. Il couId simIy be sufficienl for a crylic sIice sile lo be used. This mulalion vas
found on lhe malernaI cyslic fibrosis chromosome in an African famiIy originaling from
Cameroon. The CI-affecled chiId, a 9-year-oId girI, had no ancrealic insufficiency and no
serious Iung disease, bul suffered from aslhma. The sveal chIoride vas eIevaled (90 lo 110
mmoI er Iiler).
CITR, GLN524HIS
a gIn524-lo-his mulalion.
CITR, GLY542TIR
In a syslemalic sludy of 133 CI individuaIs in norlhern IlaIy, Gasarini el aI. (1993) found a
oinl mulalion crealing a slo codon in Iace of gIycine-542. In moIecuIar genelic anaIyses on
129 Hisanic individuaIs vilh cyslic fibrosis in lhe soulhveslern Uniled Slales, Grebe el aI.
(1994) found lhal 5.4% (7 of 129) individuaIs carried lhis mulalion.
In a alienl vilh severe ancrealic insufficiency, Gasarini el aI. (1993) found a missense
mulalion crealing a slo codon in Iace of gIulamine-552. This mulalion vas found in 3 of 225
cases.
CITR, ASI648VAL |dbSNI:rs121909033j
an as648-lo-vaI mulalion.
CITR, LYS710TIR |dbSNI:rs75115087j
oinl mulalion crealing a slo codon in Iace of Iysine-710.
Ghanem el aI. (1994) idenlified a C-lo-T subslilulion al nucIeolide 2880 in exon 15, resuIling in
a slo codon al osilion 890. This mulalion vas found in 2 reIaled Iorluguese alienls, a 13-
year-oId girI and her 15-year-oId uncIe, vho have a cIassic form of lhe disease and nasaI
oIyosis. olh alienls had I508deI on lhe olher CI chromosome, and lhe uncIe had a
osilive sveal lesl (140 mmoI er Iiler). The mulalion changed lhe reslriclion siles MseI(+) and
MboII(-).
.0100 CFTR POLYMORPHI5M
CITR, SIR912LIU |dbSNI:rs121909034j
In a sludy of 224 non-I508deI CI chromosomes, Ghanem el aI. (1994) idenlified a 2867C-T
lransilion in exon 15 of lhe CITR gene, resuIling in a ser912-lo-Ieu (S912L) subslilulion, in a CI
carrier of Irench and Sanish exlraclion. Il vas difficuIl lo redicl vhelher lhis subslilulion
vouId be deIelerious.
y in vilro funclionaI exression sludies, CIain el aI. (2005) demonslraled lhal lhe S912L
subslilulion vas nol disease-causing in isoIalion, bul significanlIy imaired CITR funclion
vhen inheriled in cis vilh anolher CITR mulalion (see 602421.0135). CIain el aI. (2005)
idenlified a heaIlhy falher of a CI felus carrying lhe S912L mulalion. A differenl CI-roducing
mulalion vas idenlified on lhe falher's olher aIIeIe. CIain el aI. (2005) concIuded lhal lhe S912L
subslilulion is a neulraI varianl.
CITR, 2-I DIL, 936TA |dbSNI:rs121908773j
ChiIIon el aI. (1994) idenlified a 2-b deIelion (TA) in exon 6b of lhe CITR gene al osilion 936
of lhe coding sequence. This frameshifl mulalion Ieads lo a remalure lerminalion codon 272
nucIeolides dovnslream and a lruncaled rolein.
CITR, HIS949TYR |dbSNI:rs121909035j
In a sludy of 224 non-I508deI CI chromosomes, Ghanem el aI. (1994) idenlified a C-lo-T
subslilulion al nucIeolide 2977 in exon 15, changing hislidine lo lyrosine al osilion 949, in a
60-year-oId voman vilh a 10-year hislory of chronic Iung disease. The sveal chIoride vaIue
vas 42 mmoI er Iiler.
CITR, LIU1065IRO |dbSNI:rs121909036j
Ghanem el aI. (1994) idenlified a T-lo-C subslilulion al nucIeolide 3326 in exon 17b, changing
Ieucine lo roIine al osilion 1065 in lhe malernaI chromosome of a 10-year-oId girI bearing a
I508deI aIIeIe. The Ieucine al lhis osilion is conserved in lhe mouse CITR rolein. This
mulalion changes lhe MnII(+) reslriclion sile. The alienl had gaslroinleslinaI and uImonary
manifeslalions of cyslic fibrosis, as veII as high sveal chIoride vaIues (66 mmoI er Iiler).
CITR, GLN1071IRO |dbSNI:rs121909037j
Ghanem el aI. (1994) idenlified an A-lo-C subslilulion al nucIeolide 3344 in exon 17b, changing
gIulamine lo roIine al osilion 1071, in a 21-year-oId voman vho, since lhe age of 5 years,
suffered from chronic gaslroinleslinaI disorders, ancrealic insufficiency, diarrhea,
slealorrhea, and very high sveal chIoride vaIues (160 mmoI er Iiler). This missense mulalion
occurs on an amino acid conserved in mouse CITR. The alienl carried lhe I508deI mulalion
on lhe olher CI chromosome. The mulalion changes lhe reslriclion sile HaeIII(+).
CITR, HIS1085ARG |dbSNI:rs79635528j
a his1085-lo-arg mulalion.
CITR, TYR1092TIR |dbSNI:rs121908761j
oinl mulalion crealing a slo codon in Iace of lyrosine-1092.
CITR, TRI1204TIR |dbSNI:rs121908764j |dbSNI:rs121908765j
Ghanem el aI. (1994) idenlified a G-lo-A subslilulion al nucIeolide 3743 in exon 19, resuIling in
a slo codon al osilion 1204. This mulalion vas found on lhe alernaI chromosome of a 4-
year-oId chiId vilh ancrealic insufficiency and a sveal chIoride IeveI of 120 mmoI er Iiler
bul no uImonary infeclion. The malernaI chromosome bears lhe I508 deIelion. The mulalion
changes lhe reslriclion siles MaeI(+).
CITR, 1-I DIL, 1215G
Romey el aI. (1994) idenlified a 1-b deIelion (G) al nucIeolide 2423 in exon 7 of lhe CITR
gene. This frameshifl mulalion Ieads lo a remalure lerminalion (UAA) 7 codons dovnslream.
The deIelion creales an AfIIII reslriclion sile and vas inheriled from lhe alienl's falher. The
alienl, a 7-year-oId boy of Irench and Sanish origin, carries a second mulalion 2423deIG
(602421.0116). Desile lhe 2 frameshifl mulalions, lhis alienl does nol resenl a severe form
of cyslic fibrosis.
CITR, THR1220ILI |dbSNI:rs1800123j
Ghanem el aI. (1994) idenlified a C-lo-T subslilulion al nucIeolide 3791 in exon 19, changing
lhreonine lo isoIeucine al osilion 1220. Il is nol knovn if lhis mulalion causes CI or is a
sequence varialion.
an iIe1234-lo-vaI mulalion.
CITR, GLY1249GLU |dbSNI:rs121909040j
GreiI el aI. (1994) idenlified a G-lo-A subslilulion al nucIeolide 3878 in exon 20, changing a
gIycine (GGG) lo gIulamic acid (GAG) al amino acid 1249.
CITR, SIR1251ASN |dbSNI:rs74503330j
a ser1251-lo-asn mulalion.
CITR, SIR1255IRO |dbSNI:rs121909041j
a ser1255-lo-ro mulalion.
CITR, ASN1303HIS |dbSNI:rs121909042j
an as1303-lo-his mulalion.
CITR, 2-I DIL, 1609CA |dbSNI:rs121908775j
a 2-b deIelion (CA) in exon 10 of lhe CITR gene.
CITR, 1-I DIL, 2423G
Romey el aI. (1994) idenlified a 1-b (G) deIelion al osilion 2423 of lhe coding sequence in
exon 13 of lhe CITR gene. This frameshifl mulalion Ieads lo a remalure lerminalion (UGA) 6
codons dovnslream. The alienl, a 7-year-oId boy of Irench and Sanish origin, carries a
second mulalion, 1215deIG (602421.0108). Desile lhe 2 frameshifl mulalions, lhis alienl does
nol resenl a severe form of cyslic fibrosis. The mulalion 2423deIG is aIso associaled vilh
sequence varialion in inlron 17a 3271+18C or T.
CITR, 1-I DIL, 3293A
Ghanem el aI. (1994) idenlified a 1-b deIelion (A) al osilion 3293 of lhe coding sequence in
exon 10 of lhe CITR gene. This frameshifl mulalion Ieads lo a remalure lerminalion codon 15
nucIeolides dovnslream and a lruncaled rolein. The alienl, a 15-year-oId I508deI
helerozygous girI of Irench origin, has a osilive sveal lesl (80 mmoI er Iiler) and ancrealic
insufficiency bul no chronic Iung infeclion.
CITR, 4-I INS, NT3667
SangiuoIo el aI. (1993) idenlified a 4-b inserlion (TCAA) al osilion 3667 of lhe coding
sequence in exon 19 of lhe CITR gene. This frameshifl mulalion Ieads lo a remalure
lerminalion codon (TGA) al amino acid osilion 1195 and deslroys a HincII reslriclion enzyme
sile. This mulalion vas found in a 20-year-oId cyslic fibrosis alienl of norlh-cenlraI IlaIian
origin vilh ancrealic insufficiency and severe uImonary invoIvemenl.
.0119 5WEAT CHLORIDE ELEVATION WITHOUT CY5TIC FIBRO5I5
CITR, SIR1455TIR |dbSNI:rs121909043j
MickIe el aI. (1998) idenlified a 6.8-kb deIelion and a nonsense mulalion (ser1455 lo ler,
S1455X) in lhe CITR gene of a molher and her youngesl daughler vilh isoIaled eIevaled sveal
chIoride concenlralions. DelaiIed cIinicaI evaIualion of bolh individuaIs found no evidence of
uImonary or ancrealic disease characlerislic of CI. A second chiId in lhis famiIy had cIassic
CI and vas homozygous for lhe 6.8-kb deIelion, indicaling lhal lhis mulalion caused severe
CITR dysfunclion. CITR mRNA lranscrils bearing lhe S1455X mulalion vere slabIe in vivo,
imIying lhal lhis aIIeIe encoded a lruncaled version of CITR missing lhe Iasl 26 amino acids.
Loss of lhis region did nol affecl rocessing of lransienlIy exressed S1455X-CITR comared
vilh viIdlye CITR. When exressed in CI airvay ceIIs, lhis mulanl generaled cAMI-
aclivaled vhoIe-ceII chIoride currenls simiIar lo viIdlye CITR. Ireservalion of chIoride
channeI funclion of lhe S1455X-CITR mulalion vas consislenl vilh normaI Iung and
ancrealic funclion in lhe molher and her daughler. The sludy indicaled lhal mulalions in
CITR can be associaled vilh eIevaled sveal chIoride concenlralions in lhe absence of lhe CI
henolye, and suggesl a reviousIy unrecognized funclionaI roIe in lhe sveal gIand for lhe
C-lerminus of CITR.
SaIvalore el aI. (2005) reorled 2 asymlomalic sislers vilh isoIaled increased sveal chIoride
concenlralions in vhom syslemalic scanning of lhe vhoIe coding region of lhe CITR gene
reveaIed comound helerozygosily for S1455X and deII508 (602421.0001).
Dork el aI. (1998) concIuded lhal lhe 3120+1G-A mulalion, vhich is resenl in African, Arab,
and a fev Greek famiIies, robabIy vas derived from a common anceslor because lhe
haIolyes are very simiIar or idenlicaI.
CITR, ARG553GLN |dbSNI:rs121909044j
In a ancreas-insufficienl alienl vilh cyslic fibrosis (219700), Dork el aI. (1991) idenlified a G-
lo-A lransilion al nucIeolide 1790 of lhe CITR gene, resuIling in an arg553-lo-gIn subslilulion.
See aIso Slern (1997).
CITR, -102T-A
See 602421.0012 and Romey el aI. (1999).
CITR, 21-K DIL
Dork el aI. (2000) described a Iarge genomic deIelion of lhe CITR gene lhal is frequenlIy
observed in CenlraI and Iaslern Iuroe. The mulalion deIeles 21,080 b sanning from inlron
1 lo inlron 3 of lhe CITR gene. Transcril anaIyses demonslraled lhal lhe deIelion resuIls in
lhe Ioss of exons 2 and 3 in eilheIiaI CITR mRNA, lhereby roducing a remalure
lerminalion signaI vilhin exon 4. A simIe ICR assay for lhe aIIeIe vas devised and used lo
screen for lhe mulalion in Iuroean and Iuroean-derived ouIalions. Some 197 CI
alienls, incIuding 7 homozygoles, vere idenlified. CIinicaI evaIualion of lhe homozygoles
and a comarison of comound helerozygoles for deII508 (602421.0001) vilh airvise-
malched deII508 homozygoles indicaled lhal lhe 21-kb deIelion reresenls a severe mulalion
associaled vilh ancrealic insufficiency and earIy age al diagnosis.
.0124 PANCREATITI5, IDIOPATHIC, 5U5CEPTIBILITY TO
HYIIRTRYISINIMIA, NIONATAL, SUSCIITIILITY TO, INCLUDID
CITR, LIU997IHI |dbSNI:rs1800111j
Gomez Lira el aI. (2000) osluIaled lhal lhere mighl be arlicuIar CITR gene mulalions
invoIved in ancrealic ducluIar obslruclion, as manifesled in idioalhic ancrealilis or in
neonalaI hyerlrysinemia. IoIIoving u on lhis hyolhesis, lhey erformed a comIele
screening of lhe CITR gene in a grou of 32 alienls vilh idioalhic ancrealilis (14 of vhom
carried lhe 5T varianl CI mulalion (602421.0086) or had a borderIine sveal chIoride IeveI, and
18 of vhom vere vilhoul common CI mulalions or any olher CI characlerislic) and in 49
nevborns vilh hyerlrysinemia and normaI sveal chIoride (32 of vhom had a common CI
mulalion, and 17 of vhom did nol have a common CI mulalion). Rare mulalions vere found
in 9 of 32 alienls vilh idioalhic ancrealilis and in 21 of 49 nevborns vilh
hyerlrysinemia. Of lhese rare mulalions, Ieu997 lo he (L997I) vas idenlified in 4 (12.5%) of
32 alienls vilh idioalhic ancrealilis and in 4 (8%) of 39 nevborns vilh hyerlrysinemia.
L997 is a highIy conserved residue in lransmembrane domain 9.
Since mosl neonalaI screening rograms for cyslic fibrosis combine lhe assay of
immunoreaclive lrysinogen (IRT) vilh anaIysis for lhe mosl common mulalions of lhe CITR
gene, lhe idenlificalion of helerozygoles among neonales because of increased IRT is
considered a dravback. Scolel el aI. (2001) assessed lhe helerozygosily frequency among
chiIdren vilh hyerlrysinemia delecled during a CI screening rogram in rillany (Irance)
10 years reviousIy. A lolaI of 160,019 babies vere screened for CI belveen 1992 and 1998. Of
lhe 1,964 nevborns vilh increased IRT (1.2%), 60 had CI and 213 vere carriers.
Helerozygosily frequency vas 12.8%, or 3 limes grealer lhan in lhe generaI ouIalion (3.9%).
A high roorlion of miId mulalions or varianls vas observed in carriers. The aIIeIic
frequency of lhe 5T varianl (5.6%) vas nol increased. The sludy vas consislenl vilh revious
ones in finding a significanlIy higher rale of helerozygoles lhan execled among neonales
vilh hyerlrysinemia.
Kabra el aI. (2000) idenlified lhe L997I mulalion in a Iakislani alienl vilh cyslic fibrosis
(219700).
Derichs el aI. (2005) reorled a chiId, born of consanguineous Turkish arenls, vho vas
homozygous for lhe L997I subslilulion. The chiId shoved normaI deveIomenl vilh no
evidence of ancrealic insufficiency or cyslic fibrosis. Sveal chIoride lesls and inleslinaI
chIoride secrelion vere normaI. Derichs el aI. (2005) concIuded lhal lhe L997I mulalion does
nol cause cyslic fibrosis.
CITR, 1-I INS, 3622T
In an Indian chiId vilh CI (219700), Kabra el aI. (2000) idenlified a 1-b inserlion (T) al
nucIeolide 3622 of lhe CITR gene.
CITR, NT3601, T-C, -20
In an Indian and a Iakislani alienl vilh CI (219700), Kabra el aI. (2000) idenlified a T-lo-C
change al osilion -20 from nucIeolide 3601 of lhe CITR gene.
CITR, 1-I DIL, 3876A |dbSNI:rs121908784j
Wang el aI. (2000) found lhal 7 of 29 Hisanic alienls vilh cyslic fibrosis (219700) vere
helerozygous for a singIe-baseair deIelion al nucIeolide 3876 (3876deIA) resuIling in a
frameshifl and lerminalion al residue 1258 (L1258X). This mulalion accounled for 10.3% of
mulanl aIIeIes in lhis grou. The alienls vilh lhis mulalion had a severe henolye as
delermined by earIy age of diagnosis, high sveal chIoride, resence of aIIergic
bronchouImonary asergiIIosis, ancrealic insufficiency, Iiver disease, cor uImonaIe, and
earIy dealh. Wang el aI. (2000) noled lhal lhis mulalion had nol been reorled in any olher
elhnic grou.
CITR, 2-I DIL, 394TT |dbSNI:rs121908769j
The 394deITT mulalion, referred lo as lhe 'Nordic mulalion,' is found al a high frequency in
lhe counlries bordering lhe aIlic Sea and associaled valervays (Sveden, Norvay, Denmark,
IinIand, Islonia, Russia, elc.). This mulalion is associaled aImosl excIusiveIy vilh a singIe
chromosomaI haIolye, vhich suggesls a singIe origin, cenlered in lhis region (Schvarlz el
aI., 1994).
CITR, HIS1282TIR
KuIczycki el aI. (2003) described lheir oIdesl alienl vilh cyslic fibrosis (219700), a 71-year-oId
vhile maIe vho had been diagnosed al lhe age of 27 years because of recurrenl nasaI
oIyosis, eIevaled sveal sodium and chIoride, and a hislory of CI in his sisler. UroIogic
examinalion demonslraled congenilaI biIaleraI absence of lhe vas deferens (277180). Al lhe age
of 60 years, genelic lesling indicaled comound helerozygosily for a severe his1282-lo-ler
(H1282X) mulalion and a miId aIa445-lo-gIu (602421.0130) mulalion in lhe CITR gene.
CITR, ALA445GLU
See 602421.0129 and KuIczycki el aI. (2003).
In a 1.5-year-oId Taivanese boy vilh cyslic fibrosis (219700), Wong el aI. (2003) found
comound helerozygosily for 2 noveI mulalions in lhe CITR gene, a G-lo-T lransversion al
nucIeolide 151 in exon 1 lhal resuIled in a gIu7-lo-ler (I7X) subslilulion in lhe firsl
lransmembrane domain of lhe rolein, and a 1-b inserlion in exon 6b (989-992insA). The
inserlion caused frameshifl and a lruncaled CITR rolein of 306 amino acids.
CITR, 1-I INS, 989A
See 602421.0131 and Wong el aI. (2003).
CITR, GLN1352HIS |dbSNI:rs113857788j
In a alienl vilh cyslic fibrosis (219700), Lee el aI. (2003) idenlified a G-lo-C lransversion al
nucIeolide 4188 in exon 22 of lhe CITR gene lhal resuIled in a gIn1352-lo-his (Q1352H) amino
acid change.
CITR, GLU217GLY |dbSNI:rs121909046j
In a alienl vilh cyslic fibrosis (219700), Lee el aI. (2003) idenlified a 782A-G lransilion in exon
6a of lhe CITR gene lhal resuIled in a gIu217-lo-gIy (I217G) amino acid subslilulion.
CITR, GLY1244VAL AND SIR912LIU
In a alienl vilh a severe form of cyslic fibrosis (219700), Savov el aI. (1995) idenlified
comound helerozygosily for mulalions in lhe CITR gene. One aIIeIe carried a G542X
subslilulion (602421.0009). The olher aIIeIe carried 2 mulalions: S912L (see 602421.0100) and a
3863G-T lransversion in exon 20, resuIling in a gIy1244-lo-vaI (G1244V) subslilulion in lhe
second nucIeolide binding domain.
y in vilro funclionaI exression sludies, CIain el aI. (2005) demonslraled lhal lhe S912L
subslilulion vas nol disease-causing in isoIalion, bul significanlIy imaired CITR funclion
vhen inheriled in cis vilh lhe G1244V mulalion. AIlhough lhe G1244V subslilulion aIone
resuIled in decreased cAMI-deendenl chIoride conduclance (43% of conlroI vaIues), lhe
G1244V/S912L comIex aIIeIe had an aImosl 20-foId reduclion in chIoride conduclion (2.4% of
conlroI vaIues) comared vilh lhe G1244V mulanl aIone.
Mendes el aI. (2003) slaled lhal an aIa561-lo-gIu (A561I) subslilulion in exon 12 of lhe CITR
gene is lhe second mosl common mulalion among Iorluguese alienls vilh cyslic fibrosis
(219700), accounling for 3% of mulanl aIIeIes. Overexression of lhe A561I mulanl rolein in
baby hamsler kidney ceIIs shoved lhal il vas misrocessed and relained in lhe endoIasmic
relicuIum, lhus beIonging lo lhe cIass II lye of CITR mulalion. Lov lemeralure lrealmenl
arliaIIy rescued a funclionaI A561I-CITR channeI, simiIar lo findings vilh lhe common
I508deI mulalion (602421.0001).
See AIso:
ayIin el aI. (1980), ChaIkIey and Harris (1991), CheadIe el aI. (1992), ChiIIon el aI. (1995),
Culling el aI. (1992), Culling el aI. (1990), Devolo el aI. (1991), de Vries el aI. (1997), Dork el aI.
(1991), Dumur el aI. (1996), Dumur el aI. (1990), Ianen el aI. (1992), Kerem el aI. (1989), Kerem
el aI. (1990), Kerem el aI. (1995), KIinger el aI. (1990), Laroche and Traverl (1991), Marino el aI.
(1991), Nunes el aI. (1992), Nunes el aI. (1991), Orila el aI. (1989), Iier el aI. (1996), Rich el aI.
(1990), RosenfeId el aI. (1992), Sheard el aI. (1993), Shoshani el aI. (1994), The Cyslic Iibrosis
Genolye-Ihenolye Consorlium (1993), Varon el aI. (1995), Yang el aI. (1993), ZieIenski el aI.
(1991)
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NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and
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Conlribulors: Ada Hamosh - udaled : 1/3/2011
Crealion Dale: Viclor A. McKusick : 3/7/1998
Idil Hislory: caroI : 04/07/2011

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