Founder Variants in KRT5 and POGLUT1 Are Implicated in Dowling-Degos Disease

Dowling-Degos disease (DDD; MIM 179850, 615327, 615696, and 613736) is a rare, autosomal dominant skin pigmentation disorder ( Degos and Ossipowski, 1954 Degos R. Ossipowski B. Dermatose pigmentaire ŕeticulée des plis (discussion de l'acanthosis nigricans) [Reticulated pigmentary dermatosis of the folds: relation to acanthosis nigricans]. Ann Dermatol Syphiligr (Paris). 1954; 81: 147-151 PubMed Google Scholar ; Dowling and Freudenthal, 1938 Dowling G.B. Freudenthal W. Acanthosis nigricans. Proc R Soc Med. 1938; 31: 1147-1150 PubMed Google Scholar ). Depending on which gene is mutated, affected individuals show progressive, reticulate hyperpigmentation that affects the trunk, face, flexures, large skin folds, genitals, and/or extremities, sometimes accompanied by pruritus. Histopathologic features encompass filiform epithelial downgrowth of the epidermal rete ridges, with deposition of melanin at the tips ( Betz et al., 2006 Betz R.C. Planko L. Eigelshoven S. Hanneken S. Pasternack S.M. Bussow H. et al. Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet. 2006; 78: 510-519 Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar ). In 2006, we identified pathogenic variants in keratin 5 (KRT5) ( Betz et al., 2006 Betz R.C. Planko L. Eigelshoven S. Hanneken S. Pasternack S.M. Bussow H. et al. Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet. 2006; 78: 510-519 Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar ) in patients with DDD who presented with hyperpigmentation in the large body folds, trunk, neck, and face. Subsequently, we and Li et al., 2013 Li M. Cheng R. Liang J. Yan H. Zhang H. Yang L. et al. Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease. Am J Hum Genet. 2013; 92: 895-903 Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar identified pathogenic variants in the genes encoding protein O-fucosyltransferase 1 ( Basmanav et al., 2015 Basmanav F.B. Fritz G. Lestringant G.G. Pachat D. Hoffjan S. Fischer J. et al. Pathogenicity of POFUT1 in Dowling-Degos disease: additional mutations and clinical overlap with reticulate acropigmentation of kitamura. J Invest Dermatol. 2015; 135: 615-618 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar ; Li et al., 2013 Li M. Cheng R. Liang J. Yan H. Zhang H. Yang L. et al. Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease. Am J Hum Genet. 2013; 92: 895-903 Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar ) and protein O-glucosyltransferase 1 (POGLUT1) ( Basmanav et al., 2014 Basmanav F.B. Oprisoreanu A.M. Pasternack S.M. Thiele H. Fritz G. Wenzel J. et al. Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease. Am J Hum Genet. 2014; 94: 135-143 Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar ; Ralser et al., 2019 Ralser D.J. Takeuchi H. Fritz G. Basmanav F.B. Effern M. Sivalingam S. et al. Altered Notch signaling in Dowling-Degos disease: additional mutations in POGLUT1 and further insights into disease pathogenesis. J Invest Dermatol. 2019; 139: 960-964 Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar ). The protein O-fucosyltransferase 1 variants were found in patients in whom hyperpigmentation involved wrists and genitals, whereas the POGLUT1 variants were found in patients in whom it involved extremities. Recently, we reported pathogenic variants in the gene presenilin enhancer, gamma-secretase subunit (PSENEN), which result in hyperpigmentation as well as, in susceptible individuals, concomitant acne inversa ( Ralser et al., 2017 Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al. Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa. J Clin Invest. 2017; 127: 1485-1490 Crossref PubMed Scopus (70) Google Scholar ).