Basmanav, F. Buket and Oprisoreanu, Ana-Maria and Pasternack, Sandra M. and Thiele, Holger and Fritz, Guenter and Wenzel, Joerg and Groesser, Leopold and Wehner, Maria and Wolf, Sabrina and Fagerberg, Christina and Bygum, Anette and Altmueller, Janine and Ruetten, Arno and Parmentier, Laurent and El Shabrawi-Caelen, Laila and Hafner, Christian and Nuernberg, Peter and Kruse, Roland and Schoch, Susanne and Hanneken, Sandra and Betz, Regina C. (2014) Mutations in POGLUT1, Encoding Protein O-Glucosyltransferase 1, Cause Autosomal-Dominant Dowling-Degos Disease. AMERICAN JOURNAL OF HUMAN GENETICS, 94 (1). pp. 135-143. ISSN 0002-9297, 1537-6605
Full text not available from this repository. (Request a copy)Abstract
Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyper-pigmentation. 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GALLI-GALLI-DISEASE; PHAGE BETA-GLUCOSYLTRANSFERASE; NOTCH SIGNALING PATHWAY; ACANTHOLYTIC VARIANT; ALAGILLE-SYNDROME; KERATIN-5; GENE; DIFFERENTIATION; FAMILY; CELLS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Nov 2019 10:43 |
| Last Modified: | 28 Nov 2019 10:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/10837 |
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