Human Molecular Genetics Advance Access originally published online on August 27, 2004
Human Molecular Genetics 2004 13(20):2377-2384; doi:10.1093/hmg/ddh276
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Human Molecular Genetics, Vol. 13, No. 20 © Oxford University Press 2004; all rights reserved
Disease associations and altered immune function in CD45 138G variant carriers
1The Edward Jenner Institute for Vaccine Research, Compton, Berkshire RG20 7NN, UK, 2Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, Cancer Research UK, John Radcliffe Hospital, Oxford OX3 9DU, UK and 3Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
Received June 28, 2004; Revised August 2, 2004; Accepted August 19, 2004
The CD45 antigen is a haemopoietic cell specific tyrosine phosphatase essential for antigen receptor mediated signalling in lymphocytes. Expression of different patterns of alternatively spliced CD45 isoforms is associated with distinct functions. We recently identified a polymorphism in exon 6 (A138G) of the gene encoding CD45 (PTPRC) that results in altered CD45 splicing. The 138G allele is present at a high frequency among Japanese (23.7%), with 5.1% individuals homozygous for the G allele. In this study we show that the A138G polymorphism is the cause of altered CD45 isoform expression, promoting splicing towards low molecular weight CD45 isoforms. We further report that the frequency of A138G heterozygotes is significantly reduced in number in cohorts of patients with autoimmune Graves' disease or hepatitis B infection, whereas G138G homozygotes are absent from a cohort of Hashimoto's thyroiditis patients. We also show that 138G individuals exhibit altered cytokine production in vitro and an increased proportion of memory T cells. These data suggest that the 138G variant allele strongly influences these diseases by modulation of immune mechanisms and may have achieved its high frequency as a result of a natural selection probably related to pathogen resistance.
* To whom correspondence should be addressed. Tel: +44 1635577929; Fax: +44 1635577901; Email: elma.tchilian{at}jenner.ac.uk
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