Germline hypomorphic CARD11 mutations in severe atopic disease

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. McElweeThomas 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

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


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.

Original languageEnglish
Pages (from-to)1192-1201
Number of pages10
JournalNature Genetics
Issue number8
StatePublished - Aug 1 2017

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