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

Publication date: Available online 26 November 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Nigel Sharfe, Ariana Karanxha, Harjit Dadi, Daniele Merico, David Chitayat, Jo-Anne Herbrick, Spencer Freeman, Sergio Grinstein, Chaim M Roifman
BackgroundWe previously reported a novel syndrome characterized by combined immunodeficiency associated with severe developmental defects - subsequently known as Roifman-Chitayat Syndrome (RCS; OMIM 613328). Linkage analysis identified two disease-associated loci.ObjectiveTo identify the genetic defect in these patients and characterize their immunological cellular abnormalities.MethodsGenetic, immunological, protein and cellular functional analyses were used to identify and characterize patient genetic deficiencies and aberrant patient cell behaviour.ResultsDeleterious variants were found at both loci identified by linkage analysis: a homozygous stop codon in PI3-kinase p110δ (PIK3CD) and a homozygous frame shift mutation in SKAP (KNSTRN), both ablating protein expression. RCS patients display aberrant B cell development, similar to p110δ deficient mice, but also aberrant T cell spreading, cell-cell interaction and migration. Patients also display significant developmental abnormalities not seen in p110δ knockouts (e.g. optic nerve atrophy, 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 MAP4 microtubule-binding protein as a novel SKAP-binding partner and show it undergoes re-localization in patient T cells, with associated areas of aberrant microtubule hyper-stabilization, likely contributing not only to the altered properties of RCS lymphoid cells but also developmental defects.ConclusionsThe complex Roifman-Chitayat Syndrome presentation, with combined developmental and immunological defects, is associated with a combined deficiency of two genes products, PI3-kinase p110δ and SKAP, both of which appear to play a significant role in the disease.

Teaser

Patients with Roifman-Chitayat syndrome suffer repeated infections due to combined immunodeficiency and display a wide array of syndromic features encompassing developmental delay, optic nerve atrophy and skeletal anomalies. We show here for the first time that complete SKAP and PI3K p110δ deficiencies lead to this complex syndrome.


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