Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease - 04/04/19

Doi : 10.1016/j.jaci.2018.08.013

Batsukh Dorjbal, PhD ^a, Jeffrey R. Stinson, PhD ^a, Chi A. Ma, PhD ^b, Michael A. Weinreich, MD ^b, Bahar Miraghazadeh, PhD ^c,^d, Julia M. Hartberger ^e, Stefanie Frey-Jakobs, PhD ^e, Stephan Weidinger, MD ^f, Lena Moebus, MSc ^f, Andre Franke, PhD ^g, Alejandro A. Schäffer, PhD ^h, Alla Bulashevska, PhD ^e, Sebastian Fuchs, PhD ^e, Stephan Ehl, MD, PhD ^e, Sandhya Limaye, PhD ⁱ, Peter D. Arkwright, FRCPCH, DPhil ^j, Tracy A. Briggs, MBChB, PhD ^j, Claire Langley, PhD ^j, Claire Bethune, MRCP, MRCPath ^k, Andrew F. Whyte, MBBS ^k, Hana Alachkar, MD ^l, Sergey Nejentsev, MD, PhD ^m, Thomas DiMaggio, RN ^b, Celeste G. Nelson, CRNP ^b, Kelly D. Stone, MD ^b, Martha Nason, PhD ⁿ, Erica H. Brittain, PhD ⁿ, Andrew J. Oler, PhD ^o, Daniel P. Veltri, PhD ^o, T. Ronan Leahy, PhD ^p, Niall Conlon, FRCPath, PhD ^q, Maria C. Poli, MD ^r, Arturo Borzutzky, MD ^s, Jeffrey I. Cohen, MD ^t, Joie Davis, APRN, APRG ^u, Michele P. Lambert, MD ^v, Neil Romberg, MD ^v, Kathleen E. Sullivan, MD, PhD ^v, Kenneth Paris, MD, PhD ^w, Alexandra F. Freeman, MD ^u, Laura Lucas, RN ^x, Shanmuganathan Chandrakasan, MD ^x, Sinisa Savic, MRCP, FRCPath ^y, Sophie Hambleton, MD, PhD ^z, Smita Y. Patel, MD, PhD, FRCPath ^aa, Michael B. Jordan, MD ^bb, Amy Theos, MD ^cc, Jeffrey Lebensburger, MD ^dd, T. Prescott Atkinson, MD ^ee, Troy R. Torgerson, MD, PhD ^ff, Ivan K. Chinn, MD ^r, Joshua D. Milner, MD ^b,^{∗
These authors contributed equally to this work.}, Bodo Grimbacher, MD ^e,^{∗
These authors contributed equally to this work.}, Matthew C. Cook, MBBS, PhD ^c,^d,^{∗
These authors contributed equally to this work.}, Andrew L. Snow, PhD ^a,^⁎^{∗
These authors contributed equally to this work.}
^a Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, Md
^b Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
ⁿ Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^o 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
^t Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^u Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
^c Department of Immunology, Canberra Hospital, Canberra, Australia
^d Centre for Personalised Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australia
^e Center for Chronic Immunodeficiency (CCI), Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^f Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
^g Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
^h National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md
ⁱ Repatriation and General Hospital, Concord, Australia
^j Paediatric Allergy and Immunology & the Manchester Center for Genomic Medicine, University of Manchester, Manchester, United Kingdom
^k Department of Clinical Immunology, Plymouth Hospitals NHS Trust, Plymouth, United Kingdom
^l Immunology, Salford Royal Foundation Trust, Manchester, United Kingdom
^m Department of Medicine, University of Cambridge, Cambridge, United Kingdom
^p Department of Paediatric Immunology and ID, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
^q Department of Immunology, St James's Hospital, Dublin, Ireland
^r Department of Pediatrics, Baylor College of Medicine, and the Section of Immunology, Allergy, and Rheumatology, Texas Children's Hospital, Houston, Tex
^s Department of Pediatrics, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
^v 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
^w Louisiana State University Health Sciences Center and Children's Hospital, New Orleans, La
^x Division of Bone Marrow Transplant, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga
^y Leeds Institute for Rheumatic and Musculoskeletal Medicine, St James University Hospital, Leeds, United Kingdom
^z Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
^aa Oxford University Hospitals NHS Trust and NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom
^bb Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio
^cc Department of Dermatology, University of Alabama at Birmingham, Birmingham, Ala
^dd Department of Pediatric Hematology Oncology, University of Alabama at Birmingham, Birmingham, Ala
^ee Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Ala
^ff University of Washington School of Medicine and Seattle Children's Hospital, Seattle, Wash

^∗Corresponding author: Andrew L. Snow, PhD, Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, C-2013, Bethesda, MD 20814.Department of Pharmacology & Molecular TherapeuticsUniformed Services University of the Health Sciences4301 Jones Bridge Rd, C-2013BethesdaMD20814

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.

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Key words : CARD11, atopy, atopic dermatitis, dominant negative, primary immunodeficiency, immune dysregulation

Abbreviations used : AD, BENTA, CARD, CC, CVID, DN, GFP, GOF, IPEX, LOF, MFI, mTORC1, NF-κB, TCR, tSNE, WES, WT

Plan

Methods

Patients

WES and genetic analysis

PBMC signaling analysis

CARD11 mutant expression plasmids

Cell transfection assays

Hierarchical clustering analysis

Unsupervised patient clustering

Statistics

Results

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

Patient phenotypes with DN CARD11 mutations

Primary cell signaling defects in CARD11 DN lymphocytes from patients

Discussion

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.

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Vol 143 - N° 4

P. 1482-1495 - avril 2019 Retour au numéro

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Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease - 04/04/19

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Conclusion

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