Germline hypomorphic CARD11 mutations in severe atopic disease

Nat Genet. 2017 Aug;49(8):1192-1201. doi: 10.1038/ng.3898. Epub 2017 Jun 19.


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.

MeSH terms

  • Amino Acid Transport System ASC / metabolism
  • CARD Signaling Adaptor Proteins / genetics*
  • Cohort Studies
  • DNA Mutational Analysis
  • Dermatitis, Atopic / genetics*
  • Dermatitis, Atopic / immunology
  • Female
  • Genes, Dominant
  • Germ-Line Mutation*
  • Glutamine / metabolism
  • Guanylate Cyclase / genetics*
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Minor Histocompatibility Antigens / metabolism
  • Multiprotein Complexes / metabolism
  • NF-kappa B / metabolism
  • Pedigree
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • TOR Serine-Threonine Kinases / metabolism


  • Amino Acid Transport System ASC
  • CARD Signaling Adaptor Proteins
  • Minor Histocompatibility Antigens
  • Multiprotein Complexes
  • NF-kappa B
  • SLC1A5 protein, human
  • Glutamine
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • CARD11 protein, human
  • Guanylate Cyclase