Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation
- Charité University Medicine, Germany
- Institut Necker Enfants Malades, INSERM U1151, CNRS UMR 8253, France
- Guangzhou Women and Children's Medical Center, China
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Germany
- Max Planck Institute for Molecular Genetics, Germany
- University of Potsdam, Germany
- Radboud University Medical Center, Netherlands
Abstract
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 mitochondrial functionality in humans.
Data availability
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Sequence Reads Archive (SRA)Publicly available at the NCBI Gene Expression Omnibus (accession no: SRP073309).
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft
- Angela M Kaindl
Charité Universitätsmedizin Berlin
- Angela M Kaindl
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States
Ethics
Animal experimentation: All animal experiments were carried out in accordance to the national ethic principles (registration no. T0344/12, Charité).
Human subjects: Informed consent was obtained from the parents of the patients for the molecular genetic analysis, the publication of clinical data, photos, magnetic resonance images (MRI), and studies on fibroblasts. The human study was approved by the local ethics committee of the Charit� (approval no. EA1/212/08).
Version history
- Received: March 24, 2016
- Accepted: July 28, 2016
- Accepted Manuscript published: August 6, 2016 (version 1)
- Version of Record published: August 19, 2016 (version 2)
Copyright
© 2016, Hartmann et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation
eLife 5:e16078.
https://doi.org/10.7554/eLife.16078
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