Loss-of-function mutations in CARD14 are associated with a severe variant of atopic dermatitis

Publication date: Available online 21 September 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Alon Peled, Ofer Sarig, Guangping Sun, Liat Samuelov, Chi A. Ma, Yuan Zhang, Tom Dimaggio, Celeste G. Nelson, Kelly D. Stone, Alexandra F. Freeman, Liron Malki, Lucia Seminario Vidal, Latha M. Chamarthy, Valeria Briskin, Janan Mohamad, Mor Pavlovski, Jolan E. Walter, Joshua D. Milner, Eli Sprecher

Abstract

Background

Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease which is known to be, at least in part, genetically determined. Mutations in CARD14 have been shown to result in various forms of psoriasis and related disorders.

Objective

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 atopic dermatitis.

Methods

Whole exome and direct gene sequencing, immunohistochemistry, real-time PCR, ELISA and functional assays in human keratinocytes were used.

Results

In a cohort of individuals referred with severe atopic dermatitis, DNA sequencing revealed in 4 patients two rare heterozygous missense mutations in CARD14 encoding the Caspase Recruitment Domain-Containing Protein 14, a major regulator of 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 patient 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.

Conclusions

While dominant gain-of-function mutations in CARD14 are associated with psoriasis and related diseases, loss-of-function mutations in the same gene are associated with a severe variant of atopic dermatitis.

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