Mutations in γ-secretase subunit–encoding PSENEN underlie Dowling-Degos disease associated with acne inversa

This study identified 6 heterozygous truncating mutations in the PSENEN gene in 6 unrelated patients and families with Dowling-Degos disease (DDD), who did not have mutations in previously known associated genes KRT5, POFUT1, and POGLUT1. The study found that these patients exhibited follicular hyperkeratosis, distinguishing them from other DDD cases. In zebrafish models, knockdown of psenen resulted in pigmentation patterns similar to human DDD, suggesting that disruptions in melanocyte migration and differentiation contribute to the disease. Additionally, 6 PSENEN mutation carriers also had acne inversa (AI), an inflammatory hair follicle disorder, often linked to nicotine abuse and obesity. This research indicated that PSENEN mutations could lead to a comanifestation of DDD and AI, with AI potentially triggered by specific predisposing factors.