Universität zu Köln

Basmanav, F. Buket, Oprisoreanu, Ana-Maria ORCID: 0000-0002-9409-0830, Pasternack, Sandra M., Thiele, Holger, Fritz, Guenter ORCID: 0000-0002-4571-8812, Wenzel, Joerg, Groesser, Leopold, Wehner, Maria, Wolf, Sabrina, Fagerberg, Christina, Bygum, Anette ORCID: 0000-0002-3004-0180, Altmueller, Janine, Ruetten, Arno, Parmentier, Laurent, El Shabrawi-Caelen, Laila, Hafner, Christian, Nuernberg, Peter, Kruse, Roland, Schoch, Susanne, Hanneken, Sandra and Betz, Regina C. (2014). Mutations in POGLUT1, Encoding Protein O-Glucosyltransferase 1, Cause Autosomal-Dominant Dowling-Degos Disease. Am. J. Hum. Genet., 94 (1). S. 135 - 144. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Basmanav, F. Buket UNSPECIFIED UNSPECIFIED UNSPECIFIED Oprisoreanu, Ana-Maria UNSPECIFIED orcid.org/0000-0002-9409-0830 UNSPECIFIED Pasternack, Sandra M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Fritz, Guenter UNSPECIFIED orcid.org/0000-0002-4571-8812 UNSPECIFIED Wenzel, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Groesser, Leopold UNSPECIFIED UNSPECIFIED UNSPECIFIED Wehner, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolf, Sabrina UNSPECIFIED UNSPECIFIED UNSPECIFIED Fagerberg, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Bygum, Anette UNSPECIFIED orcid.org/0000-0002-3004-0180 UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruetten, Arno UNSPECIFIED UNSPECIFIED UNSPECIFIED Parmentier, Laurent UNSPECIFIED UNSPECIFIED UNSPECIFIED El Shabrawi-Caelen, Laila UNSPECIFIED UNSPECIFIED UNSPECIFIED Hafner, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Kruse, Roland UNSPECIFIED UNSPECIFIED UNSPECIFIED Schoch, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Hanneken, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Betz, Regina C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-448774
DOI:	10.1016/j.ajhg.2013.12.003
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	94
Number:	1
Page Range:	S. 135 - 144
Date:	2014
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GALLI-GALLI-DISEASE; PHAGE BETA-GLUCOSYLTRANSFERASE; ACANTHOLYTIC VARIANT; NOTCH; KERATIN-5; GENE; DIFFERENTIATION; PROLIFERATION; MELANOBLASTS; SUBSTRATE Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44877