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  Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood

Vögtle, F.-N., Brändl, B., Larson, A., Pendziwiat, M., Friederich, M. W., White, S. M., et al. (2018). Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood. American Journal of Human Genetics, 102(4), 557-573. doi:10.1016/j.ajhg.2018.02.014.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0001-25D3-7 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-8E2C-D
Genre: Journal Article

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© 2018 American Society of Human Genetics
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 Creators:
Vögtle, F.-Nora, Author
Brändl, Björn1, Author              
Larson, Austin, Author
Pendziwiat, Manuela, Author
Friederich, Marisa W., Author
White, Susan M., Author
Basinger, Alice, Author
Kücükköse, Cansu, Author
Muhle, Hiltrud, Author
Jähn, Johanna A., Author
Keminer, Oliver, Author
Helbig, Katherine L., Author
Delto, Carolyn F., Author
Myketin, Lisa , Author
Mossmann, Dirk , Author
Burger, Nils, Author
Miyake, Noriko, Author
Burnett, Audrey, Author
van Baalen, Andreas , Author
Lovell, Mark A. , Author
Matsumoto, Naomichi, AuthorWalsh, Maie , AuthorYu, Hung-Chun , AuthorDeepali N. Shinde, Deepali N. , AuthorStephani, Ulrich , AuthorVan Hove, Johan L. K. , AuthorMüller, Franz-Josef2, Author              Helbig, Ingo, Author more..
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Cellular Phenotyping (Franz-Josef Müller), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014190              

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Free keywords: mitochondrial disease; mitochondrial presequence protease; mitochondrial protein biogenesis; mitochondrial targeting signal; neurodegeneration
 Abstract: Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. Introduction of the identified PMPCB variants into the homologous S. cerevisiae Mas1 protein resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters, which are indispensable for a broad range of crucial cellular functions. Analysis of biopsy materials of an affected individual revealed changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.

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Language(s): eng - English
 Dates: 2018-03-222018-04-05
 Publication Status: Published in print
 Pages: 17
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.ajhg.2018.02.014
PMID: 29576218
 Degree: -

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Title: American Journal of Human Genetics
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 102 (4) Sequence Number: - Start / End Page: 557 - 573 Identifier: ISSN: 0002-9297
CoNE: /journals/resource/954925377893