SH2D1A – X-linked lymphoproliferative syndrome

X-linked lymphoproliferative syndrome (XLP1) is a rare X-linked recessive primary immunodeficiency characterized by fatal responses to Epstein–Barr virus (EBV), hemophagocytic lymphohistiocytosis (HLH), dysgammaglobulinemia and B-cell lymphoma. The disease is caused by pathogenic variants in the SH2D1A gene, which encodes the SLAM-associated protein (SAP), critical for T and NK cell signaling via SLAM family receptors PMID:9811875.

Genetic evidence for the SH2D1A–XLP1 association includes over 100 unrelated male probands from more than 35 families with hemizygous loss-of-function or missense variants. Variant classes encompass nonsense (e.g., c.163C>T (p.Arg55Ter) PMID:9811875), frameshift (c.245dup (p.Asn82fs) PMID:28816794), splice (c.137+5G>A PMID:25491288), and missense (c.169T>C (p.Ser57Pro) PMID:14583885; c.96G>T (p.Arg32Ser) PMID:36254040). These variants segregate with disease in multiple pedigrees and arise de novo in carrier mothers.

Segregation analyses demonstrate maternal transmission in large kindreds, with at least 3 additional affected male relatives confirmed to carry the family SH2D1A variant and manifest XLP1 clinical features.

Functional studies support a loss-of-function mechanism: structural modeling and biochemical assays show that SH2D1A mutations disrupt the SAP SH2 domain, abrogating binding to SLAM and 2B4, impairing NK and CD8+ T cell cytotoxicity, and preventing proper immune regulation (PMID:11477068; PMID:10694488). Mouse Sap knockout models recapitulate key human phenotypes.

No significant conflicting evidence has been reported; genotype-phenotype correlations are limited by environmental modifiers and EBV exposure. The broad spectrum of SH2D1A variants and concordant functional data establish a definitive gene-disease relationship.

Key Take-home: SH2D1A sequencing and flow cytometric SAP expression assays are essential for diagnosis in males with EBV-associated HLH, hypogammaglobulinemia or lymphoproliferation, guiding timely genetic counseling and allogeneic stem cell transplantation.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1998 • Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome PMID:9811875
• The Journal of Biological Chemistry • 2001 • Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients PMID:11477068
• Clinical Infectious Diseases • 2003 • Fatal hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus infection in a patient with a novel mutation in the signaling lymphocytic activation molecule-associated protein PMID:14583885
• Medicine • 2022 • Potential pathogenic mechanism of type 1 X-linked lymphoproliferative syndrome caused by a mutation of SH2D1A gene in an infant: A case report PMID:36254040

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