CD45 variant alleles: possibly increased frequency of a novel exon 4 CD45 polymorphism in HIV seropositive Ugandans.

The CD45 (leucocyte common) antigen is a haemopoietic cell specific tyrosine phosphatase essential for antigen receptor signalling in lymphocytes, and expression of different CD45 isoforms is associated with distinct functions. Here we describe a novel polymorphism in exon 4 (A54G) of the gene encoding CD45 (PTPRC) that results in an amino acid substitution of Thr-19 to Ala in exon 4. The 54G allele was identified in African Ugandan populations and was found with a suggestive but not statistically significant increase in frequency amongst HIV-seropositive Ugandans. This suggests that the 54G variant and CD45 splicing abnormalities might be associated with HIV infection

A CD45 polymorphism associated with abnormal splicing is absent in African populations.

The CD45 antigen is essential for normal antigen receptor-mediated signalling in lymphocytes, and different patterns of splicing of CD45 are associated with distinct functions in lymphocytes. Abnormal CD45 splicing has been recognized in humans, caused by a C77G transversion in the gene encoding CD45 (PTPRC). Recently the C77G polymorphism has been associated with multiple sclerosis and increased susceptibility to HIV-1 infection. These studies suggest that the regulation of CD45 splicing may be critical for the proper function of the immune system. Because of these data we examined the frequency of the C77G allele in African and Asian populations from countries with high or low prevalence of HIV infection. Here we report that the variant CD45 C77G allele is absent in African populations. We further show that populations living in the Pamir mountains of Central Asia have a very high prevalence of the C77G variant

Geographical distribution and disease associations of the CD45 exon 6 138G variant.

CD45 is crucial for normal lymphocyte signalling, and altered CD45 expression has major effects on immune function. Both mice and humans lacking CD45 expression are severely immunodeficient, and single-nucleotide polymorphisms in the CD45 gene that cause altered splicing have been associated with autoimmune and infectious diseases. Recently, we identified an exon 6 A138G polymorphism resulting in an increased proportion of activated CD45RO T cells and altered immune function. Here we report a significantly reduced frequency of the 138G allele in hepatitis C Japanese patients and a possibly reduced frequency in type I diabetes. The allele is widely distributed in the Far East and India, indicating that it may have a significant effect on disease burden in a large part of the human population

Abnormal Cell Surface Antigen Expression in Individuals with Variant CD45 Splicing and Histiocytosis

Hemophagocytic lymphohistiocytosis (HLH) and Langerhans cell histiocytosis (LCH) are members of a group of rare heterogenous disorders, the histiocytoses, characterized by uncontrolled accumulation of pleomorphic infiltrates of leukocytes. The etiology of these diseases is mainly unknown. CD45 is a hemopoietic cell specific tyrosine phosphatase essential for antigen receptor mediated signaling in lymphocytes and different patterns of CD45 splicing are associated with distinct functions. Recently a polymorphism (C77G) in exon 4 of CD45 causing abnormal CD45 splicing and a point mutation affecting CD45 dimerization were implicated in multiple sclerosis in humans and lymphoproliferation and autoimmunity in mice respectively. Here we show that two patients with HLH exhibited abnormal CD45 splicing caused by the C77G variant allele, while a further 21 HLH patients have normal CD45. We have also examined 62 LCH patients and found three to have the C77G mutation. Peripheral blood thymus-derived (T) CD8+ cells from normal individuals carrying the C77G mutation show a significant decrease in the proportion of cells expressing L-selectin and increased frequency of cells with LFA-1hi expression. It remains to be established whether C77G is a contributing factor in these histiocytic disorders