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  Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival

Hucthagowder, V., Morava, E., Kornak, U., Lefeber, D. J., Fischer, B., Dimopoulou, A., et al. (2009). Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival. Human Molecular Genetics, 18(12), 2149-2165. doi:10.1093/hmg/ddp148.

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Genre: Journal Article
Alternative Title : Hum Mol Genet

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Hucthagowder, Vishwanathan, Author
Morava, Eva, Author
Kornak, Uwe1, Author              
Lefeber, Dirk J., Author
Fischer, Björn, Author
Dimopoulou, Aikaterini, Author
Aldinger, Annika, Author
Choi, Jiwon, Author
Davis, Elaine C., Author
Abuelo, Dianne N., Author
Adamowicz, Maciej, Author
Al-Aama, Jumana, Author
Basel-Vanagaite, Lina, Author
Fernandez, Bridget, Author
Greally, Marie T., Author
Gillessen-Kaesbach, Gabriele, Author
Kayserili, Hulya, Author
Lemyre, Emmanuelle, Author
Tekin, Mustafa, Author
Türkmen, Seval2, Author              
Tuysuz, Beyhan, AuthorYüksel-Konuk, Berrin, AuthorMundlos, Stefan1, Author              Van Maldergem, Lionel, AuthorWevers, Ron A., AuthorUrban, Zsolt, Author more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              

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 Abstract: Autosomal recessive cutis laxa type 2 (ARCL2), a syndrome of growth and developmental delay and redundant, inelastic skin, is caused by mutations in the a2 subunit of the vesicular ATPase H+-pump (ATP6V0A2). The goal of this study was to define the disease mechanisms that lead to connective tissue lesions in ARCL2. In a new cohort of 17 patients, DNA sequencing of ATP6V0A2 detected either homozygous or compound heterozygous mutations. Considerable allelic and phenotypic heterogeneity was observed, with a missense mutation of a moderately conserved residue p.P87L leading to unusually mild disease. Abnormal N- and/or mucin type O-glycosylation was observed in all patients tested. Premature stop codon mutations led to decreased ATP6V0A2 mRNA levels by destabilizing the mutant mRNA via the nonsense-mediated decay pathway. Loss of ATP6V0A2 either by siRNA knockdown or in ARCL2 cells resulted in distended Golgi cisternae, accumulation of abnormal lysosomes and multivesicular bodies. Immunostaining of ARCL2 cells showed the accumulation of tropoelastin (TE) in the Golgi and in large, abnormal intracellular and extracellular aggregates. Pulse–chase studies confirmed impaired secretion and increased intracellular retention of TE, and insoluble elastin assays showed significantly reduced extracellular deposition of mature elastin. Fibrillin-1 microfibril assembly and secreted lysyl oxidase activity were normal in ARCL2 cells. TUNEL staining demonstrated increased rates of apoptosis in ARCL2 cell cultures. We conclude that loss-of-function mutations in ATP6V0A2 lead to TE aggregation in the Golgi, impaired clearance of TE aggregates and increased apoptosis of elastogenic cells.

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Language(s): eng - English
 Dates: 2009-06
 Publication Status: Published in print
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Title: Human Molecular Genetics
  Alternative Title : Hum Mol Genet
Source Genre: Journal
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Publ. Info: -
Pages: - Volume / Issue: 18 (12) Sequence Number: - Start / End Page: 2149 - 2165 Identifier: ISSN: 0964-6906