Germline hypomorphic CARD11 mutations in severe atopic disease.
Nat Genet
; 49(8): 1192-1201, 2017 Aug.
Article
en En
| MEDLINE
| ID: mdl-28628108
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Mutación de Línea Germinal
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Dermatitis Atópica
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Proteínas Adaptadoras de Señalización CARD
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Guanilato Ciclasa
Tipo de estudio:
Etiology_studies
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Incidence_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Female
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Humans
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Male
Idioma:
En
Año:
2017
Tipo del documento:
Article