PSORS2 is due to mutations in CARD14

Area of Science:

• Genetics
• Immunodermatology
• Molecular Biology

Background:

• Psoriasis is a prevalent, immune-mediated genetic skin disorder often co-occurring with psoriatic arthritis.
• Previous research localized the psoriasis susceptibility locus 2 (PSORS2) to chromosome 17q25.3-qter.
• Genetic linkage of PSORS2 was observed in both European and Taiwanese families with psoriasis.

Purpose of the Study:

• To identify the specific gene responsible for PSORS2.
• To investigate the role of identified mutations in the pathogenesis of psoriasis and psoriatic arthritis.
• To elucidate the molecular mechanisms by which CARD14 mutations contribute to skin inflammation.

Main Methods:

• Genome-wide linkage scans in families with psoriasis and psoriatic arthritis.
• Genomic capture and DNA sequencing to identify mutations in candidate genes.
• Functional studies using keratinocytes to assess the impact of CARD14 mutations on NF-kB activation and gene expression.

Main Results:

• Unique gain-of-function mutations in the Caspase Recruitment Domain Family, Member 14 (CARD14) gene were identified and segregated with psoriasis.
• Specific mutations (p.Gly117Ser and p.Glu138Ala) were found to enhance nuclear factor kappa B (NF-kB) activation.
• These mutations led to the upregulation of psoriasis-associated genes, including CCL20 and IL8, in keratinocytes.

Conclusions:

• Rare gain-of-function mutations in CARD14 are a significant genetic factor in psoriasis and psoriatic arthritis.
• Mutated CARD14 initiates a cascade of inflammation by activating NF-kB and upregulating inflammatory genes in keratinocytes.
• These molecular events contribute to the characteristic cycle of epidermal inflammation and regeneration seen in psoriasis lesions.