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Loss-of-function mutations in caspase recruitment domain-containing protein 14 (CARD14) are associated with a severe
Alon Peled1, Ofer Sarig2, Guangping Sun3
1Department of Dermatology, Tel Aviv Medical Center, Tel Aviv, Israel; Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel.
Insights
Rare loss-of-function mutations in the CARD14 gene are linked to severe atopic dermatitis (AD). These mutations disrupt nuclear factor-kappa B (NF-κB) signaling, impacting skin immunity in AD patients.
Area of Science:
- Genetics
- Immunology
- Dermatology
Background:
- Atopic dermatitis (AD) is a common, genetically influenced inflammatory skin condition.
- Mutations in caspase recruitment domain-containing protein 14 (CARD14) are implicated in psoriasis and related disorders.
Purpose of the Study:
- Identify rare DNA variants associated with severe AD risk.
- Investigate the functional impact of these variants.
Main Methods:
- Whole-exome and gene sequencing.
- Immunohistochemistry and real-time PCR.
- Functional assays in human keratinocytes and ELISA.
Main Results:
- Identified two rare heterozygous missense mutations in CARD14 in severe AD patients.
- Demonstrated a dominant loss-of-function effect on NF-κB signaling.
- Observed decreased CARD14 expression and NF-κB activity markers in patient skin; keratinocytes showed altered innate immunity mediator secretion.
Conclusions:
- Loss-of-function mutations in CARD14 are associated with a severe form of atopic dermatitis.
- This contrasts with gain-of-function mutations linked to psoriasis.
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.
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