Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease that is known to be, at least in part, genetically determined. Mutations in caspase recruitment domain-containing protein 14 (CARD14) have been shown to result in various forms of psoriasis and pityriasis rubra pilaris. In this research project, we aimed to identify rare DNA variants conferring a significant risk for AD through genetic and functional studies in a cohort of patients affected with severe AD. Whole exome and direct gene sequencing revealed in 4 patients 2 rare heterozygous missense mutations in the gene encoding CARD14, a major regulator of nuclear factor κB (NF-κB). A dual luciferase reporter assay demonstrated that both mutations exert a dominant loss-of-function effect and result in decreased NF-κB signaling. Accordingly, immunohistochemistry staining showed decreased expression of CARD14 in patients' skin, as well as decreased levels of activated p65, a surrogate marker for NF-κB activity. CARD14-deficient or mutant-expressing keratinocytes displayed abnormal secretion of key mediators of innate immunity. Interestingly, CARD14 expression was also found to be reduced in the skin of patients with sporadic atopic dermatitis. In conclusion, while dominant gain-of-function mutations in CARD14 are associated with psoriasis and related diseases, dominant loss-of-function mutations in the same gene are associated with a severe variant of AD.

Dual role of CARD14 in skin inflammatory diseases