Structural basis for SH2D1A mutations in X-linked lymphoproliferative disease

X-linked lymphoproliferative disease (XLP) is a rare and severe immune defi ciency, characterized by abnormal immune responses to the Epstein-Barr viru s. Recently, the gene responsible for XLP, SH2D1A, has been identified and shown to code for a small cytoplasmic protein with an SH2 domain that inter acts with SLAM and 2B4, two receptorial molecules involved in signal transd uction in T and NK cells, respectively. A variety of SH2D1A gene mutations have been reported thus far in XLP males. Here we describe a single-strand conformation polymorphism assay for mutation analysis in XLP. Four novel pa tients with SH2D1A. mutations are described. These mutants, and the others previously reported in the literature, have been included in a Registry (SH 2D1Abase) that is fully accessible on the World Wide Web. A three-dimension al model of the SH2 domain of the SH2D1A protein has been developed, based on homology with other SH2 domains. The structural consequences of disease- causing SH2D1A mutations are discussed. (C) 2000 Academic Press.