Journal Article

Germline hypomorphic CARD11 mutations in severe atopic disease

Palma, Alejandro, Bernasconi, Andrea R, Jones, Nina, Meffre, Eric, Reynolds, Paul R, Zhang, Yu, Prieto, Emma, Cooper, Megan A, Ma, Chi A, Arjunaraja, Swadhinya, Dubra, Geronimo, DiMaggio, Thomas, Matthews, Helen F, Zaiat, Jonathan, Kim, Brian, Niemela, Julie, Rosenzweig, Sergio D, Dorjbal, Batsukh, Yamakawa, Natsuko, Abbott, Jordan K, Hauk, Pia J, Stoddard, Jennifer, Marti, Marcelo A, Danielian, Silvia, Milner, Joshua D, Glauzy, Salomé, Voss, Kelsey, Stone, Kelly D, McElwee, Joshua J, Ruffo, Elisa, Oleastro, Matías, Lyons, Jonathan J, Romberg, Neil, Weinreich, Michael A, Nelson, Celeste G, Zhang, Yuan, Snow, Andrew L, Gelfand, Erwin W, Stinson, Jeffrey R

2017

Overview

Erwin Gelfand, Andrew Snow, Joshua Milner and colleagues identify heterozygous CARD11 mutations associated with severe atopic disease in eight individuals from four families. They further show that the mutant CARD11 proteins exhibit both loss-of-function and dominant-interfering activity and that the cellular defects in patient T cells can be partially rescued by supplementing with glutamine. 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.

• Publisher: Springer New York,Nature Publishing Group
• Subject: 13/106 / 13/109 / 13/31 / 13/44 / 13/95 / 692/308/2056 / 692/699/249/1570/1622 / 692/699/249/2510/1415 / 82/29 / 82/80 / Agriculture / Allergic diseases / Amino Acid Transport System ASC - metabolism / Animal Genetics and Genomics / Atopic dermatitis / Biomedicine / Cancer Research / CARD Signaling Adaptor Proteins - genetics / Cell activation / Cell lines / Cohort Studies / Defects / Dermatitis / Dermatitis, Atopic - genetics / Dermatitis, Atopic - immunology / DNA Mutational Analysis / Eczema / Female / Food allergies / Gene Function / Gene mutation / Genes, Dominant / Genetic aspects / Germ-Line Mutation / Glutamine / Glutamine - metabolism / Guanylate Cyclase - genetics / Human Genetics / Humans / Jurkat Cells / Kinases / Lymphocyte Activation / Lymphocytes / Lymphocytes T / Male / Mechanistic Target of Rapamycin Complex 1 / Minor Histocompatibility Antigens - metabolism / Multiprotein Complexes - metabolism / Mutation / NF-kappa B - metabolism / Pedigree / Physiological aspects / Rapamycin / Receptors / Risk factors / Scaffolding / Supplements / T cell receptors / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / TOR protein / TOR Serine-Threonine Kinases - metabolism / Transfection / γ-Interferon