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J Allergy Clin Immunol. 2018 Aug 28. pii: S0091-6749(18)31201-6. doi: 10.1016/j.jaci.2018.08.013. [Epub ahead of print]

Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease.

Author information

1
Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, Md.
2
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
3
Department of Immunology, Canberra Hospital, Canberra, Australia; Centre for Personalised Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
4
Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
5
Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
6
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
7
National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md.
8
Repatriation and General Hospital, Concord, Australia.
9
Paediatric Allergy and Immunology & the Manchester Center for Genomic Medicine, University of Manchester, Manchester, United Kingdom.
10
Department of Clinical Immunology, Plymouth Hospitals NHS Trust, Plymouth, United Kingdom.
11
Immunology, Salford Royal Foundation Trust, Manchester, United Kingdom.
12
Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
13
Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
14
Bioinformatics and Computational Sciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
15
Department of Paediatric Immunology and ID, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
16
Department of Immunology, St James's Hospital, Dublin, Ireland.
17
Department of Pediatrics, Baylor College of Medicine, and the Section of Immunology, Allergy, and Rheumatology, Texas Children's Hospital, Houston, Tex.
18
Department of Pediatrics, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile.
19
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
20
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
21
Division of Immunology and Allergy, Children's Hospital of Philadelphia, and the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa.
22
Louisiana State University Health Sciences Center and Children's Hospital, New Orleans, La.
23
Division of Bone Marrow Transplant, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga.
24
Leeds Institute for Rheumatic and Musculoskeletal Medicine, St James University Hospital, Leeds, United Kingdom.
25
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
26
Oxford University Hospitals NHS Trust and NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.
27
Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
28
Department of Dermatology, University of Alabama at Birmingham, Birmingham, Ala.
29
Department of Pediatric Hematology Oncology, University of Alabama at Birmingham, Birmingham, Ala.
30
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Ala.
31
University of Washington School of Medicine and Seattle Children's Hospital, Seattle, Wash.
32
Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, Md. Electronic address: andrew.snow@usuhs.edu.

Abstract

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.

KEYWORDS:

CARD11; atopic dermatitis; atopy; dominant negative; immune dysregulation; primary immunodeficiency

PMID:
30170123
DOI:
10.1016/j.jaci.2018.08.013

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