Germline hypomorphic, dominant interfering CARD11 mutations drive severe atopic disease

Monogenic causes for serious manifestations of common allergic disease inform our mechanistic understanding of the pathogenesis of atopy. However, infections and other syndromic phenotypes often accompany such disorders. We performed next-generation sequencing on a cohort of patients with severe atopic dermatitis with evidence of familial inheritance, regardless of comorbidities. We discovered 9 individuals from 5 families harboring distinct, novel heterozygous mutations in CARD11, a lymphocyte scaffolding protein that facilitates NF-κB and mTOR signaling following antigen receptor (AgR) engagement. Significant infections beyond the skin, and non-immunologic comorbidities, were documented in some but not all patients. Improvement of skin and infectious history were noted in the majority of the patients. Each CARD11 mutant exhibited attenuated AgR-driven signaling to NF-κB and mTORC1, and dominantly interfered with the ability of WT CARD11 to activate these pathways in transfected T cell lines. Primary patient T cells also showed defects in AgR-induced activation of NF-κB and mTORC1, which is critical for promoting Th1 and preventing Th2 responses. Impaired proliferation, mTORC1 signaling and IFN-γ production were partially rescued by supplementing with excess glutamine, which requires CARD11 for import into T cells. In contrast to B cell lymphoproliferative disease associated with gain-of-function CARD11 mutations, and severe combined immunodeficiency associated with null CARD11 mutations, our new findings indicate single hypomorphic mutations in CARD11 can cause potentially correctable cellular defects that lead to severe atopy.