Combined immunodeficiency and atopy caused by a dominant negative mutation in CARD11

Publication date: Available online 19 August 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Harjit Dadi, Tyler A. Jones, Daniele Merico, Nigel Sharfe, Adi Ovadia, Yael Schejter, Brenda Reid, Mark Sun, Linda Vong, Adelle Atkinson, Sasson Lavi, Joel L. Pomerantz, Chaim M. Roifman
BackgroundCombined immunodeficiency is a T cell defect frequently presenting with recurrent infections as well as associated immune dysregulation manifesting as autoimmunity or allergic inflammation.ObjectiveWe sought to identify the genetic aberration in four related patients with combined immunodeficiency, early onset asthma, eczema and food allergies, as well as autoimmunity.MethodsWhole exome sequencing (WES) followed by Sanger confirmation, assessment of the genetic variant impact on cell signaling and evaluation of the resultant immune function.ResultsA heterozygous novel c.C88T one base pair substitution resulting in the amino acid change R30W in CARD11 was identified by WES and segregated perfectly to family members with severe atopy only, but was not found in healthy individuals. We demonstrate that the R30W mutation results in a loss of function while also exerting a dominant negative effect on wild-type CARD11. The CARD11 defect altered the classical Nuclear Factor-κB (NF-κB) pathway, resulting in poor in vitro T cell responses to mitogens and antigens caused by reduced secretion of IFNγ and IL-2.ConclusionUnlike patients with biallelic mutations in CARD11 causing severe combined immunodeficiency, the R30W defect results in a less profound yet prominent susceptibility to infections as well as multi-organ atopy and autoimmunity.

Teaser

We show here for the first time that a novel R30W dominant negative mutation in CARD11 can cause a familial autosomal dominant disorder encompassing combined immunodeficiency, severe multi-system atopy and autoimmunity.


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