Germline hypomorphic CARD11 mutations in severe atopic disease

Nat Genet. 2017 Aug;49(8):1192-1201. doi: 10.1038/ng.3898.

Chi A Ma ¹, Jeffrey R Stinson ², Yuan Zhang ¹, Jordan K Abbott ³, Michael A Weinreich ¹, Pia J Hauk ³, Paul R Reynolds ³, Jonathan J Lyons ¹, Celeste G Nelson ¹, Elisa Ruffo ² ⁴, Batsukh Dorjbal ², Salomé Glauzy ⁵, Natsuko Yamakawa ⁵, Swadhinya Arjunaraja ², Kelsey Voss ², Jennifer Stoddard ⁶, Julie Niemela ⁶, Yu Zhang ⁷, Sergio D Rosenzweig ⁶, Joshua J McElwee ⁸, Thomas DiMaggio ¹, Helen F Matthews ⁷, Nina Jones ⁹, Kelly D Stone ¹, Alejandro Palma ¹⁰, Matías Oleastro ¹⁰, Emma Prieto ¹⁰, Andrea R Bernasconi ¹⁰, Geronimo Dubra ¹⁰, Silvia Danielian ¹⁰, Jonathan Zaiat ¹⁰, Marcelo A Marti ¹⁰, Brian Kim ¹¹, Megan A Cooper ¹², Neil Romberg ¹³, Eric Meffre ⁵, Erwin W Gelfand ³, Andrew L Snow ², Joshua D Milner ¹

Affiliations

1 Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
2 Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
3 Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
4 Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
5 Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
6 Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
7 Human Immunological Disease Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
8 Merck Research Laboratories, Merck and Co., Inc., Boston, Massachusetts, USA.
9 Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, Frederick, Maryland, USA.
10 Servicio de Immunología y Reumatología, Hospital Nacional de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina.
11 Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
12 Department of Pediatrics, Division of Rheumatology and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
13 Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

PMID: 28628108 DOI: 10.1038/ng.3898

Abstract

Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ). The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis.

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