Alternative titles; symbols
SNOMEDCT: 115688004;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp22.32 | [XG blood group system, Xg(a-) phenotype] | 314700 | 3 | XGR | 314705 |
A number sign (#) is used with this entry because the XG blood group system is based on variation in the XG regulator locus (XGR; 314705) on chromosome Xp22.3, which controls erythroid expression of the XG glycoprotein (300879).
The XG blood group system is the only blood group system assigned to the X chromosome. The system consists of 2 antigens, Xg(a) and CD99, which are encoded by 2 adjacent genes, XG and CD99 (313470). Xg(a) may be expressed only on red blood cells, whereas CD99 is expressed on all tissue cells. The expression level of CD99 on red blood cells is directly related to the presence or absence of Xg(a). Both anti-Xg(a) and anti-CD99 are rare. Anti-Xg(a) is considered clinically insignificant, and the clinical significance of anti-CD99 is unknown (review by Johnson, 2011).
Mann et al. (1962) identified the first Xg(a) antiserum in a patient with hereditary hemorrhagic telangiectasia (see 187300) who had received many transfusions (Mann et al., 1962). The antigen is well developed at birth. Evidence suggested that homozygotes react as strongly with anti-Xg(a) as hemizygotes and more strongly than heterozygotes.
Thornton and Grimsley (2019) reviewed the clinical significance of antibodies to antigens in several blood group systems, including XG. Anti-Xg(a) had not been implicated in hemolytic transfusion reactions nor in hemolytic disease of the fetus or newborn. Anti-CD99 is rare, and no information regarding clinical significance for transfusion had been reported. Anti-CD99 had not been implicated in hemolytic disease of the fetus or newborn.
Mann et al. (1962) demonstrated that the Xg(a) antigen behaves as an X-linked dominant.
Mann et al. (1962) found the Xg(a) antigen in 89% of 188 Caucasian females and in 62% of 154 males. In the few Blacks tested, the phenotype frequencies seem to be about the same as in Caucasians.
The efficient estimate of the frequency of the Xg(a) allele in Caucasians, making use of the data on females as well as males, is 0.651 (Sanger et al., 1962).
In her review, Johnson (2011) stated that the XG gene, which encodes Xg(a), spans the pseudoautosomal boundary between the 2 regions of the X chromosome at Xp22.3. The MIC2 gene, which encodes CD99, is located in the pseudoautosomal region at chromosome Xp22.2, adjacent to the XG gene.
Ellis et al. (1994) proposed that the observed XG polymorphism may be due to variation in an XG regulator (XGR; 314705) that may be situated between the XG gene and the MIC2 gene (see MOLECULAR GENETICS).
Ellis et al. (1994) demonstrated that XG, which they called PBDX, a gene found to span the pseudoautosomal boundary on the X chromosome, is the XG blood group gene. Using rabbit polyclonal and mouse monoclonal antibodies raised against a peptide derived from the N-terminal domain of the predicted mature PBDX, they identified the Xg(a) antigen. By its identity with PBDX, therefore, Xg(a) was recognized as a cell-surface antigen 48% homologous to CD99. Ellis et al. (1994) concluded that the XG polymorphism is defined by a difference in the level of the Xg antigen on the surface of the erythrocyte rather than a difference in the amino acid sequences of the protein products encoded by the Xg(a) allele and an alternative Xg(a)-negative allele. They proposed a model in which the observed XG polymorphism may be due to variation in an XG regulator (XGR; 314705) that may be situated between the XG locus proximally and the MIC2 locus distally.
By comparing calculated Xg(a) frequencies in different populations with 2,612 variants in the XG region, Moller et al. (2018) found that the SNP rs311103 (314705.0001), located 3.7-kb upstream of the XG transcription start site in the proposed XGR locus, showed the strongest correlation to the expected distribution. The same SNP also had the most significant impact on XG transcript levels in whole blood (P of 2.0 x 10(-22)). The minor C allele of rs311103 disrupted a GATA1 (305371)-binding motif and silenced erythroid XG mRNA expression, causing the Xg(a-) phenotype, a finding corroborated by SNP genotyping in 158 blood donors. EMSA and mass spectrometric analysis showed that GATA1 bound to the major G allele of rs311103, but not the minor C allele, and reporter assays showed that the GATA1-binding motif was active for the G allele, but not the C allele, in human erythroleukemia cells. The authors concluded that their findings elucidated the underlying cause of the Xg blood group, providing the basis for Xg(a) genotyping.
Yeh et al. (2018) noted that high and low erythroid expression of CD99 (CD99H and CD99L, respectively) is directly related to Xg(a) expression. Among females and males, Xg(a+) is associated with CD99H, and Xg(a-) females show an association with CD99L. However, Xg(a-) males may have either the CD99H or CD99L phenotype. Using next-generation sequencing of genomic areas relevant to XG and CD99 followed by a large-scale association study, Yeh et al. (2018) independently demonstrated an association between rs311103 and Xg(a)/CD99 phenotypes. The G and C alleles of rs311103 were associated with the Xg(a+)/CD99H and Xg(a-)/CD99L phenotypes, respectively. Reporter assays showed that the rs311103 genomic region with the G genotype had strong transcription-enhancing activity specifically in erythroid lineage cells that was absent with the C genotype. Follow-up analysis showed that GATA1 could bind specifically to the G allele of rs311103 and stimulate transcriptional activity. Yeh et al. (2018) concluded that rs311103 provides the genetic basis of the erythroid-specific Xg(a)/CD99 blood group phenotypes.
Using whole genome sequencing and serologic red blood cell antigen typing, Lane et al. (2019) confirmed that rs311103 was the only SNP that correlated with the Xg(a+)/Xg(a-) phenotype. They noted that the Y chromosome PAR1 region interfered with Xg(a) typing in males.
Data on gene frequencies of XG allelic variants were tabulated by Roychoudhury and Nei (1988).
The Xg(a) blood group proved useful to genetics, especially for study of linkage (summary by Race and Sanger, 1975) and determination where nondisjunction occurs leading to X chromosome aneuploidy. Evidence on lyonization of the Xg locus was conflicting. Evidence for lyonization came from a study of X-linked hypochromic anemia (300751) by Lee et al. (1968). Lawler and Sanger (1970) found that a group of females with Philadelphia-chromosome-positive myeloid leukemia cases had the frequency of Xg types expected of females. This could mean either that the Xg locus is not subject to inactivation or that all Ph-positive cells are not monoclonal. Also assumed, of course, was that the erythroid cells in the patients studied were derived from a Ph-positive cell and that no red cells derived from Ph-negative precursors persisted. Data on linkage of the Xg locus with many other loci are summarized by Race and Sanger (1975). Ducos et al. (1971) studied a chimera twin pair in whom 2 red cell populations were easily separable because of differences in their ABO blood groups. One population was Xg(a+), the other Xg(a-). Thus the important point was established that the Xg antigen is made in the red cell precursors and not secondarily acquired by red cells. Xg can, therefore, give information on lyonization.
The Xg locus cannot be on the distal third of the long arm of the X chromosome, because Pearson (1973) observed a family in which the mother was Xg(a+) and had a balanced translocation of the distal third of the Xq onto 3p, the karyologically normal father was Xg(a-), and an unbalanced daughter with deleted distal third of the long arm of one X chromosome (derived from the mother) was Xg(a+). Bernstein et al. (1977) presented evidence from an X-Y translocation suggesting that the Xg locus is at the distal end of Xp and that an X-linked mental retardation locus is in the same region. From the study of a boy nullisomic for the terminal portion of Xp, Ferguson-Smith and Aitken (1982) concluded that the order of loci is STS (300747)--11cM--Xg--?2cM--Xk--OA. The boy showed sulfatase-deficient ichthyosis and was Xg(a-), although the family findings suggest that he should be Xg(a+), but he did not have chronic granulomatous disease or ocular albinism. On the other hand, Ropers et al. (1982) suggested the order Xg--H-Y repressor--STS--Xk. That the Xg locus is near one end of the X chromosome was suggested by the fact that it shows lack of linkage with so many loci. (The genetic length of the X chromosome is about 200 cM.) Race and Sanger (1975) pointed out that when the 3-generation linkage data for deutan (303800), protan (303900), G6PD (305900) and classic hemophilia (306700) (on the one hand) versus Xg (on the other) are pooled, the score is 236 nonrecombinants and 193 recombinants: a recombination fraction of 45% (chi square 4.3, expecting 50% recombination).
Positive evidence that Xg is in the Xp2 region comes mainly from 2 sources. In the first place, Evans et al. (1979) reported morphologic studies suggesting that about 70% of nonmosaic cases of XX males have arisen by Xp-Yp interchange in paternal meiosis. In such cases, the short arm of one X is longer, by 0.4% to 22.9%, than the short arm of the other X chromosome, and its banding profile is altered. Evans et al. (1979) found a Y-specific fragment in the DNA digest from 1 of 3 XX males with Xp+ whom they studied. Combined with this morphologic and biochemical evidence for Xp-Yp interchange are the data on Xg blood group in XX males and their parents. In 9 of 12 cases the XX male failed to inherit the Xg+ gene from his father, suggesting that the Xg locus was lost in the process of Xp-Yp interchange. These cases were not studied morphologically; thus the cases without anomaly of Xg inheritance may have had a cause other than interchange, e.g., occult mosaicism, transfer of Y material to an autosome, or perhaps an autosomal recessive gene for sex reversal. (De la Chapelle et al. (1979) could not corroborate heteromorphism of the X chromosomes in 46,XX males.) During meiosis the X and Y chromosomes show terminal association of their short arms, including an electron microscopically demonstrable synaptinemal complex. This may predispose to X-Y interchange. There should be XY individuals who are Xg-positive, even though the mother is Xg-negative, as a result of transfer of their father's Xg+ gene to the Y chromosome that he gave that particular offspring. Such persons might or might not have an abnormality of sexual development.
A second web of evidence that Xg is on Xp2 comprises (a) the linkage of Xg to X-linked ichthyosis (308100), (b) the demonstration of steroid sulfatase deficiency as the fundamental defect in X-linked ichthyosis, and (c) the assignment of the steroid sulfatase locus to Xp22-Xpter by study of deleted X chromosomes in mouse-man somatic cell hybrids (Mohandas et al., 1979). Both the Xg locus (Race and Sanger, 1975) and the steroid sulfatase locus (Mohandas et al., 1979) do not, it seems, participate in lyonization. Thus, the distal part of the short arm of the X chromosome appears to have 2 properties different from the rest of the X: pairing with the Y and absence of inactivation. Boyd et al. (1981) studied an instructive family in which the Xg(a-) mother had a 46Xt(X;Y)(p24;q11) karyotype and had transmitted her X-Y translocation chromosome to both her son and her daughter. The mother and daughter were monosomic for the region Xq24-Xqter and the son nullisomic for the same region. The maternal grandfather was Xg(a+) and neither grandparent carried the translocation chromosome. Thus, in origin of the translocation, the Xg locus was lost. The son showed generalized ichthyosis and zero steroid sulfatase activity. His mother had activity like that of normal males. Thus, the STS locus must have been involved also in the deletion of Xp. Ferguson-Smith et al. (1964) had predicted, on the basis of karyotype-phenotype correlations, that a region of Xp must escape inactivation and contain the Xg locus. Ropers et al. (1983) estimated the genetic length of the short arm of the X chromosome to be about 75-90 cM (the Xg-centromere segment). Sarfarazi et al. (1983) found no linkage between Xg and a proximal Xp DNA polymorphic marker called L1.28 (DXS7) and no close linkage between Xg and a more distal RFLP (lambda-RC8, or DXS9). Curry et al. (1984) found that the steroid sulfatase, Xg, and MIC2X loci as well as the locus for X-linked chondrodysplasia punctata (302950) were apparently absent in males with deletion of Xp22.32.
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Yeh, C.-C., Chang, C.-J., Twu, Y.-C., Chu, C.-C., Liu, B.-S., Huang, J.-T., Hung, S.-T., Chan, Y.-S., Tsai, Y.-J., Lin, S.-W., Lin, M., Yu, L.-C. The molecular genetic background leading to the formation of the human erythroid-specific Xg(a)/CD99 blood groups. Blood Adv. 2: 1854-1864, 2018. [PubMed: 30061310] [Full Text: https://doi.org/10.1182/bloodadvances.2018018879]