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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 Val602 variant of the non-synonymous single nucleotide polymorphism (SNP) rs509749 in the SLAM family member CD229 (Ly9, SLAMF3) has a two-fold lower affinity compared with the SLE-associated Met602 variant for the small adaptor protein SAP. Comparison of the two variants in T-cell lines revealed the Val602 variant to be significantly more highly expressed than CD229 Met602 . Activation was diminished in cells expressing CD229 Val602 compared with CD229 Met602 as measured by up-regulation of CD69. 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.

Original publication

DOI

10.1111/imm.12513

Type

Journal article

Journal

Immunology

Publication Date

11/2015

Volume

146

Pages

392 - 400

Keywords

CD229, SLAM, T cell, signalling, systemic lupus erythematosus, Amino Acid Motifs, Amino Acid Substitution, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, CD3 Complex, Genetic Predisposition to Disease, Genome-Wide Association Study, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, Jurkat Cells, Lectins, C-Type, Lupus Erythematosus, Systemic, Lymphocyte Activation, Phosphotyrosine, Polymorphism, Single Nucleotide, Protein Binding, Signaling Lymphocytic Activation Molecule Associated Protein, Signaling Lymphocytic Activation Molecule Family, T-Lymphocytes, src Homology Domains