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:
CreatorsEmailORCIDORCID Put Code
Fischer, BjoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dimopoulou, AikateriniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Egerer, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gardeitchik, ThatjanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kidd, AlexaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jost, DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kayserili, HulyaUNSPECIFIEDorcid.org/0000-0003-0376-499XUNSPECIFIED
Alanay, YaseminUNSPECIFIEDorcid.org/0000-0003-0683-9731UNSPECIFIED
Tantcheva-Poor, IlianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mangold, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daumer-Haas, CorneliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Phadke, ShubhaUNSPECIFIEDorcid.org/0000-0002-6624-082XUNSPECIFIED
Peirano, Reto I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heusel, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Desphande, CharuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gupta, NeerjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nanda, ArtiUNSPECIFIEDorcid.org/0000-0002-1223-3181UNSPECIFIED
Felix, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berry-Kravis, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kabra, MadhulikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wevers, Ron A.UNSPECIFIEDorcid.org/0000-0003-2278-9746UNSPECIFIED
van Maldergem, LionelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mundlos, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morava, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornak, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
H+-ATPASE; ALTERED GLYCOSYLATION; PROTEIN GLYCOSYLATION; VACUOLAR (H+)-ATPASES; MISSENSE MUTATION; BRAIN DYSGENESIS; DEBRE TYPE; CELLS; GENE; DISEASEMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48021

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