Single Gene Mutation Linked to Severe Atopic Dermatitis

Each of the four families had a distinct mutation that affected a different region of the CARD11 (Caspase recruitment domain-containing protein 11) protein, but all the mutations had similar effects on T-cell signaling.

The CARD11 gene encodes a scaffolding protein involved in lymphocyte receptor signaling. CARDs (Caspase activation and recruitment domains) are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct interactions between individual CARDs. CARD domains are found on a strikingly wide range of proteins, including helicases, kinases, mitochondrial proteins, caspases, and other cytoplasmic factors.

Transfection of the mutant CARD11gene into T-cell lines grown in laboratory culture demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor–induced activation of nuclear factor-kappaB and mammalian target of rapamycin complex 1 (mTORC1). Patient T-cells had similar defects, as well as low production of the cytokine interferon-gamma (IFN-gamma). The mTORC1 and IFN-gamma production defects were partially rescued by supplementation with the amino acid glutamine, which requires CARD11 for import into T-cells.

This study was carried out by the [U.S.] National Institute of Allergy and Infectious Diseases (Bethesda, MD, USA) and was published in the June 19, 2017, online edition of the journal Nature Genetics.

Related Links:
National Institute of Allergy and Infectious Diseases