Dorjbal, B, Stinson, JR, Ma, CA et al. (52 more authors) (2019) Hypomorphic CARD11 mutations associated with diverse immunologic phenotypes with or without atopic disease. The Journal of Allergy and Clinical Immunology, 143 (4). pp. 1482-1495. ISSN 0091-6749
Abstract
CARD11 encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to NF-κB, JNK, and mTORC1. Germline CARD11 mutations cause several distinct primary immune disorders in humans, including SCID (biallelic null mutations), B cell Expansion with NF-κB and T cell Anergy (BENTA; heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by whole exome sequencing.To determine the molecular actions of an extended allelic series of CARD11, and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles.Cell transfections and primary T cell assays were utilized to evaluate signaling and function of CARD11 variants.Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in STAT3-LOF, DOCK8 deficiency, common variable immune deficiency (CVID), neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)-like syndrome. Pathogenic variants exhibited dominant negative activity, and were largely confined to the CARD or coiled-coil domains of the CARD11 protein.These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in humans, and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an author produced version of a paper published in Journal of Allergy and Clinical Immunology. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | CARD11; atopy; atopic dermatitis; dominant negative; primary immunodeficiency; immune dysregulation |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 24 Sep 2018 16:48 |
Last Modified: | 28 Aug 2019 00:43 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.jaci.2018.08.013 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:135712 |