Alt. symbols: IMD5 | LYP | XLP | MTCP1 | DSHP | XLPD | EBVS | SAP

Approved name: SH2 domain containing 1A
Alt. names: lymphoproliferative syndrome, SH2 domain protein 1A | Duncan's disease

Location: Xq25: 124227868 - 124373197 (+)
Gene type: protein_coding, 16 transcripts.

Scores: LoFtool: 0.413000 | pLI: 0.08260881 | LOEUF: 0.959

HGNC: 10820

NCBI: 4068, RefSeq: NG_007464.1

Ensembl: ENSG00000183918.18

LRG_106 | Status: public

OMIM: 300490

Expression | ProteinAtlas

SH2D1A encodes SLAM-associated protein (SAP), a regulator of lymphocyte survival and NK T cell development. SAP acts as a molecular switch to prevent the association of other SH2 binding proteins (i.e. SHP2) with phosphoTyrosine motifs on SLAM and 2B4 receptors on stimulated T and NK cells, respectively. Thus, SAP LOF is thought to engender an uncontrolled immune response to EBV or other viral infections secondary to dysregulated SLAM and/or 2B4 signaling. Thus, it helps to regulate lymphocytes that destroy cytotoxic lymphocytes and is necessary for the development of natural killer T cells. However, because these receptors are also highly expressed on B-cells and SLAM plays a role in B-cell proliferation and Ig synthesis, SH2D1A may also lead to B-cell intrinsic defects in addition to secondary defects from interactions with abnormal T and NK cells (PMID: 9091591). SAP also helps to control immune reactions by triggering apoptosis of lymphocytes when they are no longer needed.

At least 70 different SH2D1A mutations have been identified in individuals with X-linked lymphoproliferative syndrome 1 (XLP1) [OMIM:308240], characterized by severe immune dysregulation due to inappropriate lymphocyte survival and tissue infiltration, often triggered by EBV infection. Severe manifestations include fatal mononucleosis, HLH, and/or malignant lymphoma, in addition to aplastic anemia or pure red cell aplasia, and lymphomatoid granulomatosis. Some mutations impair SAP function, whil e others result in unstable or absent protein. The link between SAP deficiency and CVID phenotypes is also well-recognized, with at least 28 patients identified to date. As early as 2000, Gilmour et al. reported mutations abrogating SAP expression in 3 patients with CVID phenotypes who did not show evidence of EBV infection at the time of initial investigation (PMID: 10898506). Interestingly, Morra et al. (2001) described incomplete penetrance in the form of one asymptomatic male mutation carrier, and one family in which the affected males showed progressively worsening hypogammaglobulinemia, but multiple female carriers demonstrated elevated IgA levels and defective specific antibody responses, consistent with prior findings for some male XLP patients (PMID: 1683154, 11520777). Nistala et al. (2001) identified absent SAP protein in 3 CVID patients (but mutations in only 2) with recurrent sinopulmonary infections, severe panhypogammaglobulinemia, CD4:CD8 ratio reversal, undetectable EBV serologies and viral loads (until one developed HLH), but variable trajectories of B cell loss (PMID: 11678908). Three more patients were reported by Soresina et al. (2002) and Aghamohammadi et al. (2003), both of whom emphasized the importance of retaining a high index of suspicion for XLP in CVID patients, even those without evidence of EBV infection, and performing molecular testing given the management differences and severe outcomes associated with XLP (PMID: 12447665, 12894850). However, Eastwood et al. (2004) identified only one SAP-deficient individual in a screen of undifferentiated 60 male CVID and PAD patients, suggesting that additional clinical features may be needed to heighten suspicion (PMID: 15320910). Subsequent additional SAP mutations have been identified in CVID patients by large-scale genetic screening (PMID: 27577878, 29709555, 31942606). [Load More]