Some of the signaling outcomes mediated by SAP rely on the ability of SAP to interact with Src-family kinases (eg, FYN, LCK), which further phosphorylate SLAM-R tyrosines and other downstream signaling molecules. Deletions and nonsense mutations were virtually always associated with absence of SAP, whereas missense and splice site mutations led to absent or decreased SAP expression. SAP protein analysis by flow cytometry was performed in a significant proportion of patients. The remaining mutations identified were nonsense, small insertion/deletion, missense, and splice site mutations expected to affect the SH2 domain. Gross deletions involving 1 or more exons were found in 15 patients from 13 families, accounting for nearly 25% of all SH2D1A mutations observed.
Mutations were found in 56 patients (16%) from 49 families, including 16 previously unreported mutations ( Figure 1A). Between 20, SH2D1A mutational analysis has been performed on samples from 360 patients referred to the Diagnostic Center for Heritable Immunodeficiencies (DCHI) at Cincinnati Children's Hospital Medical Center because of a suspected diagnosis of XLP as determined by referring physicians. Today, more than 70 mutations resulting in XLP1 have been reported to the Human Gene Mutation Database (HGMD), and more are probable to emerge. In this review, we describe the genetic, clinical, and immunopathologic features of these 2 disorders and discuss current diagnostic and therapeutic strategies. Beyond their common X-linked locus and their requirement for normal immune responses to certain viral infections, SAP and XIAP demonstrate no obvious structural or functional similarity, are not coordinately regulated with respect to their expression, and do not appear to directly interact.
For both forms of XLP, the only curative therapy at present is allogeneic hematopoietic cell transplantation.
To date, XLP2 has been found to cause HLH with and without exposure to Epstein-Barr virus, and HLH is commonly recurrent in these patients. XLP1 is a disease with multiple and variable clinical consequences, including fatal hemophagocytic lymphohistiocytosis (HLH) triggered predominantly by Epstein-Barr virus, lymphomas, antibody deficiency, and rarer consequences of immune dysregulation. Signaling lymphocytic activation molecule-associated protein (SAP encoded by SH2D1A) is mutated in XLP1, and X-linked inhibitor of apoptosis (XIAP encoded by BIRC4) is mutated in XLP2. X-linked lymphoproliferative disease (XLP1), described in the mid-1970s and molecularly defined in 1998, and XLP2, reported in 2006, are prematurely lethal genetic immunodeficiencies that share susceptibility to overwhelming inflammatory responses to certain infectious triggers.