Germline hypomorphic CARD11 mutations in severe atopic disease

MA, CHI A.; STINSON, JEFFREY R.; ZHANG, YUAN; ABBOTT, JORDAN K.; WEINREICH, MICHAEL A.; HAUK, PIA J.; REYNOLDS, PAUL R.; LYONS, JONATHAN J.; NELSON, CELESTE G.; RUFFO, ELISA; DORJBAL, BATSUKH; GLAUZY, SALOMÉ; YAMAKAWA, NATSUKO; ARJUNARAJA, SWADHINYA; VOSS, KELSEY; STODDARD, JENNIFER; NIEMELA, JULIE; ZHANG, YU; ROSENZWEIG, SERGIO D.; MCELWEE, JOSHUA J.; DIMAGGIO, THOMAS; MATTHEWS, HELEN F.; JONES, NINA; STONE, KELLY D.; PALMA, ALEJANDRO; OLEASTRO, MATÍAS; PRIETO, EMMA; BERNASCONI, ANDREA R.; DUBRA, GERONIMO; DANIELIAN, SILVIA; ZAIAT, JONATHAN; MARTI, MARCELO A.; KIM, BRIAN; COOPER, MEGAN A.; ROMBERG, NEIL; MEFFRE, ERIC; GELFAND, ERWIN W.; SNOW, ANDREW L.; MILNER, JOSHUA D.

NATURE GENETICS

NATURE PUBLISHING GROUP

Año: 2017 vol. 49 p. 1192 - 1201

1061-4036

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.