Bianca Hartmann, Timothy Wai, Hao Hu, Thomas MacVicar, Luciana Musante, Björn Fischer-Zirnsak, Werner Stenzel, Ralph Gräf, Lambert van den Heuvel, Hans-Hilger Ropers, Thomas F. Wienker, Christoph Hübner, Thomas Langer, Angela M. Kaindl
- Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrialMitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans.…
MetadatenAuthor details: | Bianca Hartmann, Timothy Wai, Hao Hu, Thomas MacVicar, Luciana Musante, Björn Fischer-Zirnsak, Werner Stenzel, Ralph GräfORCiDGND, Lambert van den Heuvel, Hans-Hilger Ropers, Thomas F. Wienker, Christoph Hübner, Thomas Langer, Angela M. Kaindl |
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DOI: | https://doi.org/10.7554/eLife.16078 |
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ISSN: | 2050-084X |
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Title of parent work (English): | eLife |
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Publisher: | eLife Sciences Publications |
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Place of publishing: | Cambridge |
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Publication type: | Article |
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Language: | English |
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Year of first publication: | 2016 |
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Publication year: | 2016 |
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Release date: | 2020/03/22 |
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Tag: | OPA1; YME1L1; intellectual disability; mitochondrial fragmentation; mitochondriopathy; optic atrophy |
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Volume: | 5 |
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Number of pages: | 37 |
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First page: | 1156 |
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Last Page: | 1165 |
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Funding institution: | German Research Foundation [SFB665, KO2891/1-1]; Berlin Institute of Health (BIH) [CRG1]; Sonnenfeld Stiftung; German Society for Muscle diseases (DGM); German Academic Exchange Service (DAAD); NCRR [P20-RR016453]; Robert C. Perry Fund [20061479]; Max-Planck Society; EU [241995]; Human Frontiers Science Program |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
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Peer review: | Referiert |
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