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

    March 2017 in “ Journal of Clinical Investigation ”
    Damian J. Ralser, F. Buket Basmanav, Aylar Tafazzoli, Jade Wititsuwannakul, Sarah Delker, Sumita Danda, Holger Thiele, Sabrina Wolf, Michélle Busch, Susanne Pulimood, Janine Altmüller, Peter Nürnberg, Didier Lacombe, Uwe Hillen, Joerg Wenzel, Jorge Frank, Benjamin Odermatt, Regina C. Betz
    Studysummary In this study, researchers identified PSENEN mutations that can lead to a form of Dowling-Degos disease, characterized by follicular hyperkeratosis and an increased susceptibility to acne inversa, especially in the presence of certain trigger factors. Our plain-language summary of this paper — not a Tressless recommendation.
    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.
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