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A polymorphism in a phosphotyrosine signalling motif of CD 229 (Ly9, SLAMF 3) alters SH 2 domain binding and T‐cell activation
Author(s) -
Margraf Stefanie,
Garner Lee I.,
Wilson Timothy J.,
Brown Marion H.
Publication year - 2015
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12513
Subject(s) - single nucleotide polymorphism , biology , signal transducing adaptor protein , snp , locus (genetics) , peripheral blood mononuclear cell , immune system , innate immune system , microbiology and biotechnology , gene , genetics , genotype , in vitro
Summary Signalling lymphocyte activation molecule ( SLAM ) family members regulate activation and inhibition in the innate and adaptive immune systems. Genome‐wide association studies identified their genetic locus (1q23) as highly polymorphic and associated with susceptibility to systemic lupus erythematosus ( SLE ). Here we show that the Val 602 variant of the non‐synonymous single nucleotide polymorphism ( SNP ) rs509749 in the SLAM family member CD 229 (Ly9, SLAMF 3) has a two‐fold lower affinity compared with the SLE ‐associated Met 602 variant for the small adaptor protein SAP . Comparison of the two variants in T‐cell lines revealed the Val 602 variant to be significantly more highly expressed than CD 229 Met 602 . Activation was diminished in cells expressing CD 229 Val 602 compared with CD 229 Met 602 as measured by up‐regulation of CD 69. There was no correlation between homozygosity at rs509749 and activation in peripheral blood mononuclear cells from healthy donors. These findings identify potential mechanisms by which a single SNP can perturb fine‐tuning in the immune system with significant functional consequences.