Mutations in Gamma-Secretase Subunit-Encoding PSENEN Underlie Dowling-Degos Disease Associated with Acne Inversa

The study identified six heterozygous truncating mutations in the PSENEN gene in patients with Dowling-Degos disease (DDD) who did not have mutations in previously known DDD-related genes. These mutations were associated with a novel histopathological feature of follicular hyperkeratosis and were also found in patients with acne inversa (AI), an inflammatory hair follicle disorder. The research suggested that PSENEN mutations could lead to a comanifestation of DDD and AI, likely triggered by factors such as nicotine abuse and obesity. Zebrafish models showed that PSENEN mutations affect melanocyte migration and differentiation, contributing to DDD pathogenesis. The study highlighted the role of Notch signaling in skin pigmentation and differentiation, suggesting that PSENEN mutations create a distinct subtype of DDD with increased susceptibility to AI.