Missense mutations in SH2D1A identified in patients with X-linked lymphoproliferative disease differentially affect the expression and function of SAP.

X-linked lymphoproliferative disease (XLP) is an immunodeficiency resulting from mutations in SH2D1A, which encodes signalling lymphocytic activation molecule (SLAM)-associated protein (SAP). In addition to SLAM, SAP associates with several other cell-surface receptors including 2B4 (CD244), Ly9 (CD229), CD84 and NTB-A. SAP contains a single src-homology-2 domain and acts as an intracellular adaptor protein by recruiting the protein tyrosine kinase FynT to the cytoplasmic domains of some of these receptors, which results in the initiation of specific downstream signal transduction pathways. XLP is likely to result from perturbed signalling through one or more of these SAP-associating receptors. In this study, we identified missense (Y54C, I84T and F87S) and insertion (fs82 --> X103) mutations in four different kindreds affected by XLP. Each mutation dramatically reduced the half-life of SAP, thus diminishing its expression in primary lymphocytes as well as in transfected cell lines. Interestingly, although the Y54C and F87S mutations compromised the ability of SAP to associate with different receptors, the I84T mutation had no effect on the ability of SAP to bind SLAM, CD84 or 2B4. However, signalling downstream of SLAM was reduced in the presence of SAP bearing the I84T mutation. These findings indicate that, irrespective of the type of mutation, signalling through SAP-associating receptors in XLP can be impaired by reducing the expression of SAP, the ability of SAP to bind surface receptors and/or its ability to activate signal transduction downstream of the SLAM-SAP complex.