title: Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease.
abstract: 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.
authors.affiliation: Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.
authors.forename: F Buket
authors.initials: FB
authors.lastname: Basmanav
authors.affiliation: Department of Neuropathology and Department of Epileptology, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Oprisoreanu
authors.affiliation: Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Pasternack
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, D-50931 Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Department of Neuropathology, Neurozentrum, University of Freiburg, D-79106 Freiburg, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Fritz
authors.affiliation: Department of Dermatology, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Wenzel
authors.affiliation: Department of Dermatology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Leopold
authors.initials: L
authors.lastname: Größer
authors.affiliation: Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Wehner
authors.affiliation: Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Wolf
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, DK-5000 Odense, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Fagerberg
authors.affiliation: Department of Dermatology and Allergy Centre, Odense University Hospital, DK-5000 Odense, Denmark.
authors.forename: Anette
authors.initials: A
authors.lastname: Bygum
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, D-50931 Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Laboratory of Dermatohistopathology, D-88048 Friedrichshafen, Germany.
authors.forename: Arno
authors.initials: A
authors.lastname: Rütten
authors.affiliation: Department of Dermatology, Berne University Hospital, CH-3008 Berne, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Parmentier
authors.affiliation: Department of Dermatology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Laila
authors.initials: L
authors.lastname: El Shabrawi-Caelen
authors.affiliation: Department of Dermatology, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hafner
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, D-50931 Cologne, Germany; Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Dermatological Practice, D-33098 Paderborn, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Kruse
authors.affiliation: Department of Neuropathology and Department of Epileptology, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schoch
authors.affiliation: Department of Dermatology, University Hospital Düsseldorf, D-40225 Düsseldorf, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hanneken
authors.affiliation: Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany. Electronic address: regina.betz@uni-bonn.de.
authors.forename: Regina C
authors.initials: RC
authors.lastname: Betz
mesh_terms: D000293:Adolescent; D000328:Adult; D059472:Exome; D005260:Female; D055106:Genome-Wide Association Study; D005964:Glucosyltransferases / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D017495:Hyperpigmentation / Q000235:genetics*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D012867:Skin / Q000473:pathology; D012873:Skin Diseases, Genetic / Q000235:genetics*; D017444:Skin Diseases, Papulosquamous / Q000235:genetics*; D055815:Young Adult
chemical_list: D005964:Glucosyltransferases; C510651:POGLUT1 protein, human