Germline hypomorphic CARD11 mutations in severe atopic disease.

MA CA, STINSON JR, ZHANG Y, ABBOTT JK, WEINREICH MA, HAUK PJ, REYNOLDS PR, LYONS JJ, NELSON CG, RUFFO E; DANIELIAN S, ZAIAT J, MARTI MA; DIMAGGIO T, MATTHEWS HF, JONES N, STONE KD, PALMA A, OLEASTRO M, PRIETO E, BERNASCONI AR, DUBRA G; DORJBAL B, GLAUZY S, YAMAKAWA N, ARJUNARAJA S, VOSS K, STODDARD J, NIEMELA J, ZHANG Y, ROSENZWEIG SD, MCELWEE JJ; KIM B, COOPER MA, ROMBERG N, MEFFRE E, GELFAND EW, SNOW AL, MILNER JD

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.