1 Dermato-venerology and Allergy Centre, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU2 ORCA, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU3 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU4 University of Bonn5 University of Cologne6 University of Freiburg7 University of Regensburg.8 Laboratory of Dermatohistopathology, D-88048 Friedrichshafen, Germany.9 Department of Dermatology, Berne University Hospital, CH-3008 Berne, Switzerland.10 Department of Dermatology, Medical University of Graz, A-8036 Graz, Austria.11 Dermatological Practice, D-33098 Paderborn, Germany.12 Department of Dermatology, University Hospital Düsseldorf, D-40225 Düsseldorf, Germany.13 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU14 Dermato-venerology and Allergy Centre, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU
Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4(∗)), c.652C>T (p.Arg218(∗)), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218(∗)) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology.
American Journal of Human Genetics, 2014, Vol 94, Issue 1, p. 135-43