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The mutation that leads to FXS is a CGG polymorphic repeat at the 5 untranslated region
(UTR) of the FMR1 gene, located at Xq27.3. The repeat expansion length of CGG determines
the how the individual is affected. Normal individuals have 6 to 54 polymorphic copies, female
carriers and normal transmitting males (NTMs) bears 55 to 200 repeats (categorized as a premutation) and when the expansion is larger than 200 repeats, it is considered as a full-mutation
and the individual might present features of mental retardation and other phenotype
characteristics. The mutation is passed between generations, were a NTM does not transmit the
gene to his male offspring but to his female daughter, and the mother can transmit both to his son
or daughter, and the mutation might be given with expansion, increasing exponentially according
to the number of repeats from the mothers allele. Full-mutation expansion only occurs when
transmitted by a female carrier, once the full-mutation males only carries pre-mutation alleles in
their sperm. When carrying the full-mutation, the gene sequence becomes abnormally methylated
and the gene is silenced. The absence of the FMR1 gene protein must be the cause of the mental
retardation, since it is a single gene based syndrome (JIN, P.; WARREN, S. T., 2000;
PENAGARIKANO, O. et. al., 2007; SHERMAN, S. et. al., 2008).
To understand how the FMRP causes mental retardation, this protein has been
extensively studied in the past several years. The main phenotype of fragile X syndrome, mental
retardation, is in the Central Nervous System (CNS), the question is: What is the function of FMRP
is in CNS, and how its absence leads to mental deficit? Based on the findings from the last
decade, it has been speculate that FMRP plays a role in the transportation of mRNAs from
nucleus to cytoplasm in neurons (crucially in dendrites), and also regulates the protein synthesis
at that local, by being part of polyribosome complexes. The regulation of protein synthesis in the
dendrites allows synaptic development and plasticity, seeing that synaptic plasticity is essential
for promotion of memory and learning processes, the last observations on the physiological role
of FMRP explains how the mutation generates the syndrome (penagakioke Crawford, outros).
The molecular mechanism for the trinucleotide repeat expansion is still unclear. It is believed that
this phenomenon is likely due to a mechanism of slipping-strand mispairing during DNA
replication in the Okazaki fragments (PENAGARIKANO, O. et. al., 2007).
REFERENCES
Crawford, D. C. et. al. FMR1 and the fragile syndrome: Human genome
epidemiology review. Genetics in Medicine. Vol. 3, n. 5, pg. 359-371, 2001.
Garber, K. B. et. al. Fragile X syndrome. Nature and European Journal of
Human Genetics. N. 16, pg. 666-672, 2008.
Jin, P.; Warren, S. T. Understanding the molecular basis of fragile X
syndrome. Human Molecular Genetics. Vol. 9, n. 6, pg. 901-908, 2000.
Penagarikano, O. et. al. The pathophysiology of Fragile X Syndrome. Annual
Review of Genomics and Human Genetics. N. 8, pg. 109-129, 2007.
Sherman, S. et. al. Fragile X syndrome: Diagnostic and carrier testing.
Genetics in Medicine. Vol. 7, n. 8, pg. 584-587, 2008.