JOHN MILTON HAGEN BLOOD GROUP SYSTEM

JMH BLOOD GROUP SYSTEM

Phenotype-Gene Relationships
Location

Phenotype

15q24.1

[Blood group, John-Milton-Hagen system]

TEXT
A number sign (#) is used with this entry because the John Milton Hagen
(JMH) blood group system is based, at least partly, on variation in the gene
encoding semaphorin-7A (SEMA7A; 607961) on chromosome 15q22.2-q23.

Description
JMH blood group antigens are carried by SEMA7A, a membraneassociated protein that plays important roles in the nervous system and
immune responses. Three different JMH phenotypes have been identified
based on the presence or absence of the high-frequency JMH (or JMH1)
antigen: JMH-weak, JMH-negative, and JMH-variant. The JMH-weak and
-negative phenotypes can be either acquired or inherited and are
characterized by a reduction or complete loss of JMH expression on red
blood cells (RBCs), often with concomitant occurrence of JMH antibodies.
Acquired JMH-weak or -negative phenotypes are typically found in elderly
persons and can be transient. The JMH antibodies present in the acquired
phenotypes have autoimmune characteristics and are clinically irrelevant.
The inherited JMH-negative phenotype has been found in only 1 family.
Mechanisms underlying the JMH-weak and -negative phenotypes have yet
to be identified. Individuals with the JMH-variant phenotype are usually
JMH-positive and have alloantibodies compatible with JMH-negative
RBCs. The JMH-variant phenotype results from rare missense mutations in
the SEMA7A gene (summary by Seltsam et al. (2007) and Richard et al.
(2011)).

Clinical Features
Seltsam et al. (2007) identified 3 different RBC phenotypes with unusual

JMH expression in 33 of 44 individuals with abnormal JMH blood groups

and their family members. Eleven individuals had a JMH-variant
phenotype lacking single JMH epitopes, 18 individuals had a JMHnegative phenotype, and 4 individuals had a JMH-weak phenotype. In
most cases, these JMH phenotypes were associated with the presence of
JMH or JMH-like antibodies in serum. The 11 remaining individuals, who
were family members of individuals with JMH-variant or JMH-negative
phenotypes, had normal JHM blood groups.
JMH-Variant Phenotype
Seltsam et al. (2007) identified 5 propositi with JMH-variant phenotype
from Canada, Germany, Japan, Poland, and the U.S. The JMH-variant
phenotype was also present in 6 of 14 family members of the propositi.
Determination of variant JMH status was based on variably positive or
negative reactions of RBCs with anti-JMH serum samples. JMH-like
antibodies were only present in the serum of the propositi, which reacted
positive with all but JMH-negative RBCs, the propositus's own RBCs, and
RBCs of compatible JMH-positive sibs.
JMH-Negative Phenotype
Seltsam et al. (2007) identified 18 individuals with JMH-negative
phenotype from Canada, Germany, Israel, Sweden, Switzerland, and the
U.S. The ages of the RBH-negative individuals, as far as known, ranged
from 54 to 82 years. The JMH-negative phenotype was identified by
negative reaction of the individuals' RBCs with JMH antisera from
immunized patients. In addition, no JMH antigen was detected on the
surface of JMH-negative RBCs by flow cytometric and immunoblot
analyses. JMH antibodies were detected in 14 of the JMH-negative
individuals. Four JMH-negative individuals belonged to an apparently
healthy family in which the JMH-negative phenotype had been detected in
3 generations. The other JMH-negative individuals were unrelated and
information about inheritance was not available. However, in 2 of these
individuals, who were apparently healthy, JMH-negative status had
remained stable over decades, excluding the transient JMH-negative

phenotype. RT-PCR analysis of total mRNA from peripheral blood cells of

JMH-negative individuals revealed normal expression of SEMA7A.
Peripheral B lymphocytes from JMH-negative individuals could be
stimulated to express normal levels of SEMA7A, and reticulocytes from
JMH-negative individuals exhibited normal expression of SEMA7A. RBCs
of JMH-negative individuals showed normal expression of other GPIlinked membrane proteins, excluding deficient biosynthesis of the GPI
anchor as the basis for loss of SEMA7A on RBCs. Seltsam et al.
(2007)concluded that the JMH-negative phenotype results from an
autoimmune-related and/or RBC lineage-specific posttranscriptional or
posttranslational mechanism.
JMH-Weak Phenotype
Seltsam et al. (2007) identified 4 individuals with RBH-weak phenotype.
RBCs from these individuals exhibited weak reactions with JMH
antibodies, and JMH antibodies were present in serum samples. In 2
individuals, RBCs produced a weakly positive direct antiglobulin test.
Three of the JMH-weak individuals were over 50 years of age, and the
fourth was a 32-year-old pregnant woman. The pregnant woman displayed
variable SEMA7A expression during pregnancy, and her baby was born
without any symptoms of hemolytic disease of the fetus or newborn.

Inheritance
JMH-Variant Phenotype
By family studies, including extended genomic sequencing, Seltsam et al.
(2007) found that the JMH-variant phenotype was inherited in an
autosomal recessive fashion in 5 families.
JMH-Negative Phenotype
Seltsam et al. (2007) noted that the JMH-negative phenotype, which is
typically acquired rather than inherited, was present in 3 generations of an
apparently healthy family. They confirmed this finding and concluded that
autosomal dominant inheritance was likely.

Mapping
The SEMA7A gene, which encodes the protein carrying the JHM antigens,
was mapped to chromosome 15q22.2-q23 by Lange et al. (1998).

Molecular Genetics
JMH-Variant Phenotype
In 5 unrelated individuals with JMH-variant phenotype from 5 different
countries, Seltsam et al. (2007) identified 4 missense mutations in the
SEMA7A gene (607961.0001-607961.0004). These mutations were not
detected in genomic DNA from 100 randomly selected individuals from
Northern Germany. All 4 missense mutations occurred in the semaphorin
domain of SEMA7A. Studies with JMH-variant RBCs and transfectants
expressing membrane-anchored recombinant SEMA7A proteins showed
that the variant SEMA7A proteins were of normal length and were
expressed at levels equal to those of the wildtype protein. In inhibition
studies with soluble recombinant wildtype and variant SEMA7A proteins,
JMH-like alloantibodies of JMH-variant individuals did not react with the
related recombinant variant SEMA7A protein, but they did react with the
wildtype and unrelated variant SEMA7A proteins, indicating that
expression of variant JMH antigen is based on the absence of certain
SEMA7A epitopes. Serologic compatibility testing of JMH-variant blood
samples confirmed these results.
In 4 young Native American women with JMH-negative phenotype from a
reservation northwest of Quebec City, Canada, Richard et al.
(2011)identified a novel missense mutation in the SEMA7A gene
(607961.0005). At least 2 of the women were JHM-positive and their
alloantibody was compatible with most JHM-negative RBCs tested; the
other 2 women were not tested. Soluble forms of wildtype and R347L
variant SEMA7A proteins were produced in vitro and demonstrated a
specific alloantibody reaction with wildtype recombinant SEMA7A, but
not with the R347L variant form.
JMH-Negative Phenotype

Seltsam et al. (2007) found that JMH-negative individuals lacked

phenotypically relevant mutations in the coding region or promoter of the
SEMA7A gene. They concluded that the JMH-negative phenotype does not
result from variation in the SEMA7A gene.
JMH-Weak Phenotype
Seltsam et al. (2007) found that JMH-weak individuals lacked
phenotypically relevant mutations in the SEMA7A gene. They concluded
that the JMH-weak phenotype does not result from variation in the
SEMA7A gene.

REFERENCES
Lange, C., Liehr, T., Goen, M., Gebhart, E., Fleckenstein, B., Ensser,
A.New eukaryotic semaphorins with close homology to semaphorins
of DNA viruses. Genomics 51: 340-350, 1998. [PubMed: 9721204, related
1. citations] [Full Text]
Richard, M., St-Laurent, J., Perreault, J., Long, A., St-Louis, M. A new
SEMA7A variant found in Native Americans with alloantibody. Vox
Sang. 100: 322-326, 2011. [PubMed: 20854351, related citations] [Full
2. Text]
Seltsam, A., Strigens, S., Levene, C., Yahalom, V., Moulds, M., Moulds, J.
J., Hustinx, H., Weisbach, V., Figueroa, D., Bade-Doeding, C., DeLuca, D.
S., Blasczyk, R. The molecular diversity of Sema7A, the semaphorin
that carries the JMH blood group antigens. Transfusion 47: 133-146,
3. 2007. [PubMed: 17207242, related citations] [Full Text]