2. Academic Validation
  3. Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation

Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation

  • Elife. 2016 Aug 6;5:e16078. doi: 10.7554/eLife.16078.
Bianca Hartmann 1 2 3,  Timothy Wai 4,  Hao Hu 5 6,  Thomas MacVicar 4,  Luciana Musante 5,  Björn Fischer-Zirnsak 5 7,  Werner Stenzel 8,  Ralph Gräf 9,  Lambert van den Heuvel 10,  Hans-Hilger Ropers 5,  Thomas F Wienker 5,  Christoph Hübner 2,  Thomas Langer 4,  Angela M Kaindl 1 2 3
Affiliations

Affiliations

  • 1 Institute of Cell Biology and Neurobiology, Charité University Medicine, Berlin, Germany.
  • 2 Department of Pediatric Neurology, Charité University Medicine, Berlin, Germany.
  • 3 Sozialpädiatrisches Zentrum (SPZ), Center for Chronically Sick Children, Charité University Medicine, Berlin, Germany.
  • 4 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Cologne, Germany.
  • 5 Max Planck Institute for Molecular Genetics, Berlin, Germany.
  • 6 Guangzhou Women and Children's Medical Center, Guangzhou, China.
  • 7 Institut of Medical Genetics and Human Genetics, Charité University Medicine, Berlin, Germany.
  • 8 Institute of Neuropathology, Charité University Medicine, Berlin, Germany.
  • 9 Department of Cell Biology, University of Potsdam, Potsdam, Germany.
  • 10 Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, Nijmegen, Netherlands.
PMID: 27495975 DOI: 10.7554/eLife.16078
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.

Keywords

OPA1; YME1L1; human; human biology; intellectual disability; medicine; mitochondrial fragmentation; mitochondriopathy; mouse; optic atrophy.

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