Potential pathogenic mechanism of type 1 X-linked lymphoproliferative syndrome caused by a mutation of SH2D1A gene in an infant: A case report.

Background: X-linked lymphoproliferative syndrome (XLP) is a rare X-linked recessive inborn errors of immunity. The pathogenesis of XLP might be related to phophatidylinositol-3-kinase (PI3K)-associated pathways but insight details remain unclear. This study was to study an infant XLP-1 case caused by a mutation in SH2D1A gene, investigate the structural and functional alteration of mutant SAP protein, and explore the potential role of PI3K-associated pathways in the progression of XLP-1.

Methods: The proband's condition was monitored by laboratory and imagological examinations. Whole exome sequencing and Sanger sequencing were performed to detect the genetic disorder. Bioinformatics tools including PolyPhen-2, SWISS-MODEL and SWISS-PDB Viewer were used to predict the pathogenicity and estimate structural change of mutant protein. Flow cytometry was used to investigate expression of SAP and PI3K-associated proteins.

Results: The proband was diagnosed with XLP-1 caused by a hemizygous mutation c.96G > T in SH2D1A gene resulting in a missense substitution of Arginine to Serine at the site of amino acid 32 (p.R32S). The mutant protein contained a hydrogen bond turnover at the site of mutation and was predicted to be highly pathogenic. Expression of SH2D1A encoded protein SAP was downregulated in proband. The PI3K-AKT-mTOR signaling pathway was fully activated in XLP-1 patients, but it was inactive or only partially activated in healthy people or HLH patients.

Conclusions: The mutation c.96G > T in SH2D1A gene caused structural and functional changes in the SAP protein, resulting in XLP-1. The PI3K-AKT-mTOR signaling pathway may play a role in XLP-1 pathogenesis.