Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis

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 Pavlovsky, Jolan E. Walter, Joshua D. Milner*, Eli Sprecher

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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 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 AD. 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 patients referred with severe AD, DNA 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. Conclusions: Although 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 AD.

Original languageEnglish
Pages (from-to)173-181.e10
JournalJournal of Allergy and Clinical Immunology
Volume143
Issue number1
DOIs
StatePublished - Jan 2019

Funding

FundersFunder number
Ram family foundation
National Institutes of Health
National Institute of Allergy and Infectious DiseasesZIAAI001247
Jeffrey Modell Foundation
University of South Florida
Gamba Family Foundation

    Keywords

    • Atopic dermatitis
    • CARD14
    • nuclear factor κB
    • psoriasis

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