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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Peled, Alon^1,2  Sarig, Ofer¹  Sun, Guangping³  Samuelov, Liat^1,2  Ma, Chi A.³  Zhang, Yuan³  Dimaggio, Tom³  Nelson, Celeste G.³  Stone, Kelly D.³  Freeman, Alexandra F.⁴  Malki, Liron¹  Vidal, Lucia Seminario⁵  Chamarthy, Latha M.^6,7  Briskin, Valeria¹  Mohamad, Janan^1,2  Pavlovsky, Mor¹  Walter, Jolan E.⁸  Milner, Joshua D.³  Sprecher, Eli^1,2 

[1] Tel Aviv Med Ctr & Sch Med, Dept Dermatol, Tel Aviv, Israel

[2] Tel Aviv Univ, Dept Human Mol Genet & Biochem, Tel Aviv, Israel

[3] NIAID, Lab Allerg Dis, NIH, 10 Ctr Dr,Room 11N240A, Bethesda, MD 20892 USA

[4] NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[5] Univ S Florida, Dept Dermatol, Tampa Bay, FL USA

[6] Johns Hopkins All Childrens Hosp, Univ South Florida, Div Pediat Allergy Immunol, St Petersburg, FL USA

[7] Adv Allergy & Asthma Care, Pinellas Pk, FL USA

[8] Massachusetts Gen Hosp Children, Boston, MA USA

关键词: Atopic dermatitis;    psoriasis;    CARD14;    nuclear factor kappa B;   

DOI  :  10.1016/j.jaci.2018.09.002

来源: Elsevier

【 摘 要 】

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 kappa B (NF-kappa B). A dual luciferase reporter assay demonstrated that both mutations exert a dominant loss-of-function effect and result in decreased NF-kappa B 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-kappa B 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.

【 授权许可】

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