Universität zu Köln

Fischer, Bjoern, Dimopoulou, Aikaterini, Egerer, Johannes, Gardeitchik, Thatjana, Kidd, Alexa, Jost, Dominik, Kayserili, Hulya ORCID: 0000-0003-0376-499X, Alanay, Yasemin ORCID: 0000-0003-0683-9731, Tantcheva-Poor, Iliana, Mangold, Elisabeth, Daumer-Haas, Cornelia, Phadke, Shubha ORCID: 0000-0002-6624-082X, Peirano, Reto I., Heusel, Julia, Desphande, Charu, Gupta, Neerja, Nanda, Arti ORCID: 0000-0002-1223-3181, Felix, Emma, Berry-Kravis, Elisabeth, Kabra, Madhulika, Wevers, Ron A. ORCID: 0000-0003-2278-9746, van Maldergem, Lionel, Mundlos, Stefan, Morava, Eva and Kornak, Uwe (2012). Further characterization of ATP6V0A2-related autosomal recessive cutis laxa. Hum. Genet., 131 (11). S. 1761 - 1774. NEW YORK: SPRINGER. ISSN 0340-6717

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Abstract

Autosomal recessive cutis laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debr, type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H+-ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications. In these individuals we identified 17 ATP6V0A2 mutations, 14 of which are novel. Furthermore, we demonstrate a localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in patients' dermal fibroblasts. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB or PYCR1. Furthermore, fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-beta signalling and increased TGF-beta 1 levels in the supernatant. Our current findings expand the genetic and phenotypic spectrum and suggest that, besides the known glycosylation defect, alterations in trafficking and signalling processes are potential key events in the pathogenesis of ATP6V0A2-related ARCL.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fischer, Bjoern UNSPECIFIED UNSPECIFIED UNSPECIFIED Dimopoulou, Aikaterini UNSPECIFIED UNSPECIFIED UNSPECIFIED Egerer, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Gardeitchik, Thatjana UNSPECIFIED UNSPECIFIED UNSPECIFIED Kidd, Alexa UNSPECIFIED UNSPECIFIED UNSPECIFIED Jost, Dominik UNSPECIFIED UNSPECIFIED UNSPECIFIED Kayserili, Hulya UNSPECIFIED orcid.org/0000-0003-0376-499X UNSPECIFIED Alanay, Yasemin UNSPECIFIED orcid.org/0000-0003-0683-9731 UNSPECIFIED Tantcheva-Poor, Iliana UNSPECIFIED UNSPECIFIED UNSPECIFIED Mangold, Elisabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Daumer-Haas, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Phadke, Shubha UNSPECIFIED orcid.org/0000-0002-6624-082X UNSPECIFIED Peirano, Reto I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heusel, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Desphande, Charu UNSPECIFIED UNSPECIFIED UNSPECIFIED Gupta, Neerja UNSPECIFIED UNSPECIFIED UNSPECIFIED Nanda, Arti UNSPECIFIED orcid.org/0000-0002-1223-3181 UNSPECIFIED Felix, Emma UNSPECIFIED UNSPECIFIED UNSPECIFIED Berry-Kravis, Elisabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Kabra, Madhulika UNSPECIFIED UNSPECIFIED UNSPECIFIED Wevers, Ron A. UNSPECIFIED orcid.org/0000-0003-2278-9746 UNSPECIFIED van Maldergem, Lionel UNSPECIFIED UNSPECIFIED UNSPECIFIED Mundlos, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Morava, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Kornak, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-480218
DOI:	10.1007/s00439-012-1197-8
Journal or Publication Title:	Hum. Genet.
Volume:	131
Number:	11
Page Range:	S. 1761 - 1774
Date:	2012
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	0340-6717
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language H+-ATPASE; ALTERED GLYCOSYLATION; PROTEIN GLYCOSYLATION; VACUOLAR (H+)-ATPASES; MISSENSE MUTATION; BRAIN DYSGENESIS; DEBRE TYPE; CELLS; GENE; DISEASE Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48021