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  Further characterization of ATP6V0A2-related autosomal recessive cutis laxa

Fischer, B., Dimopoulou, A., Egerer, J., Gardeitchik, T., Kidd, A., Jost, D., et al. (2012). Further characterization of ATP6V0A2-related autosomal recessive cutis laxa. Human Genetics, 131(11), 1761-1773. doi:10.1007/s00439-012-1197-8.

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Fischer, B., Author
Dimopoulou, A., Author
Egerer, J.1, Author           
Gardeitchik, T., Author
Kidd, A., Author
Jost, D., Author
Kayserili, H., Author
Alanay, Y., Author
Tantcheva-Poor, I., Author
Mangold, E., Author
Daumer-Haas, C., Author
Phadke, S., Author
Peirano, R. I., Author
Heusel, J., Author
Desphande, C., Author
Gupta, N.2, Author           
Nanda, A., Author
Felix, E., Author
Berry-Kravis, E., Author
Kabra, M., Author
Wevers, R. A., Authorvan Maldergem, L., AuthorMundlos, S.3, Author           Morava, E., AuthorKornak, U.3, Author            more..
Affiliations:
1Former Research Groups, Max Planck Institute of Biochemistry, Max Planck Society, München, Germany, ou_1565145              
2Algorithms and Complexity, MPI for Informatics, Max Planck Society, Saarbrücken, Germany, ou_24019              
3Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, Berlin, Germany, ou_1433557              

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Free keywords: Adolescent Adult Apoptosis Blotting, Western Brefeldin A/pharmacology Cells, Cultured Child, Preschool Cutis Laxa/ congenital/genetics/metabolism/pathology Enzyme-Linked Immunosorbent Assay Fibroblasts/drug effects/metabolism/pathology Fluorescent Antibody Technique Glycosylation/drug effects Golgi Apparatus/drug effects/metabolism Humans Infant Male Mutation/ genetics Protein Synthesis Inhibitors/pharmacology Protein Transport/drug effects Proton-Translocating ATPases/ genetics RNA, Messenger/genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Skin/drug effects/metabolism/pathology Transforming Growth Factor beta1/ metabolism Young Adult
 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), Debre 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-beta1 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.

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Language(s): eng - English
 Dates: 2012-07-082012-11
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1007/s00439-012-1197-8
 Degree: -

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Title: Human Genetics
Source Genre: Journal
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Publ. Info: Berlin : Springer-Verlag
Pages: - Volume / Issue: 131 (11) Sequence Number: - Start / End Page: 1761 - 1773 Identifier: ISSN: 0340-6717
CoNE: https://pure.mpg.de/cone/journals/resource/954925519623