Dual loss of p110δ PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features

摘要

BackgroundWe previously reported a novel syndrome characterized by combined immunodeficiency associated with severe developmental defectssubsequently known as Roifman-Chitayat syndrome (RCS; OMIM613328). Linkage analysis identified 2 disease-associated loci.ObjectivesWe sought to identify the genetic defect in these patients and characterize their immunologic cellular abnormalities.MethodsGenetic, immunologic, protein, and cellular functional analyses were used to identify and characterize patient genetic deficiencies and aberrant patient cell behavior.ResultsDeleterious variants were found at both loci identified by linkage analysis: a homozygous stop codon in PI3-kinase p110?(PIK3CD) and a homozygous frame shift mutation in SKAP (KNSTRN), both ablating protein expression. Patients with RCS display aberrant B-cell development, similar to p110?deficient mice, but also aberrant T-cell spreading, cell-cell interaction, and migration. Patients also display significant developmental abnormalities not seen in p110?knockouts (eg, optic nerve atrophy and skeletal anomalies) that we ascribe to loss of SKAP. Aberrant SKAP expression can prolong anaphase and this may contribute to developmental defects. However, we also identified microtubule-associated protein 4 microtubule-binding protein as a novel SKAP-binding partner and show that it undergoes relocalization in patient T燾ells, with associated areas of aberrant microtubule hyperstabilization, likely contributing not only to the altered properties of RCS lymphoid cells but also to developmental defects.ConclusionsThe complex RCS presentation, with combined developmental and immunologic defects, is associated with a combined deficiency of 2 genes products, PI3-kinase p110?and SKAP, both of which appear to play a significant role in the disease.