CD99, the product of the MIC2 gene, exhibits an erythroid-specific quantitative 
polymorphism co-regulated with the Xga blood group polymorphism. The 
co-expression of X-linked MIC2 and XG genes is presumably controlled at the 
transcriptional level by a single XGR locus in the pseudoautosomal region of 
sexual chromosomes. This locus is composed of two alleles, XGR(low) and 
XGR(high), which determine low or high CD99 levels (CD99-L, CD99-H) and the 
Xg(a-)/ Xg(a+) status. To test this hypothesis, the phenotypic relationship 
between Xga and CD99 antigens on human RBCs was investigated by quantitative 
flow cytometry using NBL-1 (anti-Xga) and 12E7 (anti-CD99) monoclonal antibodies 
and semi-quantitative estimate of membrane proteins and RNA by Western blot and 
Northern blot, respectively. The antibody binding capacity of RBCs, which is an 
estimation of the antigen density, was determined for 118 blood donors including 
60 males and 58 females. Xg(a+) RBCs, which all belong to the group of CD99-H 
expressors, carry 159+/-13 and 960+/-50 copies of Xga and CD99 molecules/cell, 
respectively. Xg(a-) RBCs have no Xga antigen, but are subdivided into CD99-H 
(all male) and CD99-L expressors carrying 747+/-28 and 200+/-22 CD99 
copies/cell, respectively, with identical CD99 levels between CD99-L males and 
females. However, among males, the CD99 expression was higher in Xg(a+) than in 
Xg(a-)/CD99-H individuals (P<0.01). In addition, CD99-H expressors in Xg(a+) 
males could be clearly subdivided into two categories, high and super high 
expressors, which are presumably heterozygous and homozygous for the XGR(high) 
allele, which fits the above hypothesis. This was not the case for Xg(a+) 
females where CD99-H subcategories were not found. Quantitative differences were 
confirmed by Western blot analysis of red cell membrane preparations from 
individuals of different Xga and CD99 phenotypes and by Northern blot analysis 
showing that the reticulocytes from CD99-L individuals expressed a reduced level 
of MIC2 transcripts compared to CD99-H donors. These findings further support 
the hypothesis of a single genetic control of CD99 and Xga expression by the XGR 
locus.