Title |
Germline hypomorphic CARD11 mutations in severe atopic disease
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Published in |
Nature Genetics, June 2017
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DOI | 10.1038/ng.3898 |
Pubmed ID | |
Authors |
Chi A Ma, Jeffrey R Stinson, Yuan Zhang, Jordan K Abbott, Michael A Weinreich, Pia J Hauk, Paul R Reynolds, Jonathan J Lyons, Celeste G Nelson, Elisa Ruffo, Batsukh Dorjbal, Salomé Glauzy, Natsuko Yamakawa, Swadhinya Arjunaraja, Kelsey Voss, Jennifer Stoddard, Julie Niemela, Yu Zhang, Sergio D Rosenzweig, Joshua J McElwee, Thomas DiMaggio, Helen F Matthews, Nina Jones, Kelly D Stone, Alejandro Palma, Matías Oleastro, Emma Prieto, Andrea R Bernasconi, Geronimo Dubra, Silvia Danielian, Jonathan Zaiat, Marcelo A Marti, Brian Kim, Megan A Cooper, Neil Romberg, Eric Meffre, Erwin W Gelfand, Andrew L Snow, Joshua D Milner |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 11 | 39% |
Spain | 2 | 7% |
United Kingdom | 2 | 7% |
Australia | 2 | 7% |
France | 1 | 4% |
Israel | 1 | 4% |
Italy | 1 | 4% |
Unknown | 8 | 29% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 15 | 54% |
Scientists | 10 | 36% |
Science communicators (journalists, bloggers, editors) | 2 | 7% |
Practitioners (doctors, other healthcare professionals) | 1 | 4% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 1 | <1% |
Unknown | 165 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 27 | 16% |
Student > Ph. D. Student | 26 | 16% |
Student > Master | 15 | 9% |
Student > Bachelor | 13 | 8% |
Other | 10 | 6% |
Other | 30 | 18% |
Unknown | 45 | 27% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 27 | 16% |
Biochemistry, Genetics and Molecular Biology | 25 | 15% |
Immunology and Microbiology | 23 | 14% |
Agricultural and Biological Sciences | 22 | 13% |
Business, Management and Accounting | 2 | 1% |
Other | 16 | 10% |
Unknown | 51 | 31% |