SH2D1A gene: function, mutations, and associated diseases | NCBI, UniProt, OMIM

SH2D1A encodes the SLAM-associated protein (SAP), a small SH2 domain-containing adaptor protein expressed predominantly in T cells, NK cells, and some B cells. SAP binds to the cytoplasmic tail of SLAM family receptors (e.g., SLAM, CD244, NTB-A) and recruits the tyrosine kinase FYN, thereby modulating immune cell signaling, cytokine production, and cytotoxicity. Loss-of-function mutations in SH2D1A cause X-linked lymphoproliferative disease type 1 (XLP1), characterized by severe immune dysregulation, including fulminant infectious mononucleosis, hypogammaglobulinemia, and lymphoma.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• SLAM family signaling pathway (Reactome: R-HSA-2871837)

• FYN-mediated signaling (Reactome: R-HSA-354192)

• NK cell mediated cytotoxicity (KEGG: hsa04650)

• T cell receptor signaling pathway (KEGG: hsa04660)

The SH2D1A-encoded SAP protein (128 amino acids, ~15 kDa) consists of a single SH2 domain and a short C-terminal tail. It binds with high affinity to tyrosine-phosphorylated motifs in the cytoplasmic tails of SLAM family receptors (SLAM, CD244, NTB-A, CD84, Ly9). SAP recruits the Src family kinase FYN via a unique interaction surface, enabling downstream signaling that regulates T cell and NK cell activation, cytokine production, and cytotoxicity. SAP deficiency leads to impaired immune responses, particularly against EBV, resulting in XLP1.