Dowling-Degos disease is a skin pigmentation disorder characterized by small dark brown, partly hyperkeratotic spots and papules located in certain areas of the body. It is a genetically very heterogeneous disorder, and underlying mutations have been described in three genes (KRT5, POFUT1 and POGLUT1). Researchers now report in the Journal of Clinical Investigations on dominant de novo mutations in PSENEN in patients with Dowling-Degos disease. PSENEN encodes the presinilin enhancer protein 2. Comprehensive functional analyses performed in this study provide fascinating insights into the molecular pathogenesis of the disorder. The results suggest that disturbed migration and differentiation of melanocytes play an important role in the development of the Dowling-Degos disease. Interestingly, patients harboring a PSENEN mutation often also present with a specific type of acne (acne inversa) so that the authors assume that PSENEN dysfunction also predisposes to inflammation of hair follicles.