Mechanisms of allergy/immunology
Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease

https://doi.org/10.1016/j.jaci.2018.08.013Get rights and content

Background

Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (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 using whole-exome sequencing.

Objectives

We sought 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.

Methods

Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants.

Results

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 signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked–like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein.

Conclusion

These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects 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.

Section snippets

Patients

Informed consent was obtained from all participating patients and their family members according to protocols approved by institutional review and ethics boards at their respective institutions.

WES and genetic analysis

WES was performed in the majority of patients described here, according to established protocols. For example, kindreds 6, 19, and 29 were analyzed as follows. Genomic DNA was extracted from peripheral blood cells, and the Illumina paired-end genomic DNA sample preparation kit (PE-102-1001; Illumina, San

Novel DN CARD11 mutations detected in a broad spectrum of immune disorders

Rare or novel CARD11 mutations were identified by allergy and primary immunodeficiency referral centers in patients with immune-deficient or dysregulatory phenotypes (Table I). A total of 48 new patients in 27 families with 26 different heterozygous germline CARD11 variants were referred. Salient patient phenotypes, combined with those already reported,7, 9 are summarized in Tables I and II. These alleles were then evaluated at centers specializing in CARD11 biology and associated diseases and

Discussion

In this report we describe multiple new DN CARD11 mutations associated with additional immunodeficient and dysregulatory conditions in human patients. Recent reports identified DN CARD11 mutations in a handful of patients presenting with severe AD and other allergic conditions with or without additional infections.7, 9 The substantially larger cohort assembled here illuminates a broader phenotypic spectrum of disease tied to CARD11 DN mutations, including frequent sinopulmonary infections,

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    Supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID), National Library of Medicine; German BMBF grants 01E01303 and 01ZX1306F; the DZIF (TTU 07.801); NIAID extramural award R21AI109187; the SFB1160 (IMPATH); and National Health and Medical Research Council (Australia) grants 1113577 and 1079648.

    Disclosure of potential conflict of interest: S. Ehl receives research support from BMBF, the Canadian Immunodeficiency Society, and the European Union's Horizon 2020 Research and Innovation Programme; serves as a consultant for UCD and Novartis but not in the context of this study; and received payments from lectures for CSL Behring. P. D. Arkwright receives travel support from Allergy Therapeutics and Nutricia. T. R. Leahy serves as a consultant for Baxalta. N. Conlon received payment for lectures from Baxalta, Novartis, and GlaxoSmithKline and received travel funds from Baxalta. T. R. Torgerson has consultant arrangements with Baxalta Biosciences, CSL Behring, and ADMA Biosciences; has received grants from Baxalta Biosciences, CSL Behring, and the National Institutes of Health (NIH); and has received payment for lectures from Baxalta Biosciences, CSL Behring, Questcor Pharmaceuticals, and the Robert Wood Johnson Foundation. B. Grimbacher receives grant support from BMBF, the European Union, Helmholtz, DFG, DLR, and DZIF; is an employee of UKL-FR; and receives payments for lectures from CSL-Behring, Baxalta, Shire, Biotest, Octopharma, Kedrion, and Grifols. M. C. Cook has received research support from the National Health and Medical Research Council, Australia. A. L. Snow receives grant support from the NIH. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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