2. Academic Validation
  3. USMG5 Ashkenazi Jewish founder mutation impairs mitochondrial complex V dimerization and ATP synthesis

USMG5 Ashkenazi Jewish founder mutation impairs mitochondrial complex V dimerization and ATP synthesis

  • Hum Mol Genet. 2018 Oct 1;27(19):3305-3312. doi: 10.1093/hmg/ddy231.
Emanuele Barca 1,  Rebecca D Ganetzky 2 3,  Prasanth Potluri 4,  Marti Juanola-Falgarona 1,  Xiaowu Gai 5 6,  Dong Li 7,  Chaim Jalas 8,  Yoel Hirsch 9,  Valentina Emmanuele 1,  Saba Tadesse 1,  Marcello Ziosi 1,  Hasan O Akman 1,  Wendy K Chung 10,  Kurenai Tanji 11,  Elizabeth M McCormick 2,  Emily Place 6,  Mark Consugar 6,  Eric A Pierce 6,  Hakon Hakonarson 2 3 7,  Douglas C Wallace 4 12,  Michio Hirano 1,  Marni J Falk 2 3
Affiliations

Affiliations

  • 1 Department of Neurology, H. Houston Merritt Neuromuscular Research Center, Columbia University Medical Center, New York, NY, USA.
  • 2 Mitochondrial Medicine Frontier Program, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 3 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Department of Pathology, Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 5 Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, LA, USA.
  • 6 Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
  • 7 Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 8 Bonei Olam, New York, NY, USA.
  • 9 Dor Yeshorim, Brooklyn, NY, USA.
  • 10 Department of Pediatrics and Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA.
  • 11 Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA.
  • 12 Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
PMID: 29917077 DOI: 10.1093/hmg/ddy231
Abstract

Leigh syndrome is a frequent, heterogeneous pediatric presentation of mitochondrial oxidative phosphorylation (OXPHOS) disease, manifesting with psychomotor retardation and necrotizing lesions in brain deep gray matter. OXPHOS occurs at the inner mitochondrial membrane through the integrated activity of five protein complexes, of which complex V (CV) functions in a dimeric form to directly generate adenosine triphosphate (ATP). Mutations in several different structural CV subunits cause Leigh syndrome; however, dimerization defects have not been associated with human disease. We report four Leigh syndrome subjects from three unrelated Ashkenazi Jewish families harboring a homozygous splice-site mutation (c.87 + 1G>C) in a novel CV subunit disease gene, USMG5. The Ashkenazi population allele frequency is 0.57%. This mutation produces two USMG5 transcripts, wild-type and lacking exon 3. Fibroblasts from two Leigh syndrome probands had reduced wild-type USMG5 mRNA expression and undetectable protein. The mutation did not alter monomeric CV expression, but reduced both CV dimer expression and ATP synthesis rate. Rescue with wild-type USMG5 cDNA in proband fibroblasts restored USMG5 protein, increased CV dimerization and enhanced ATP production rate. These data demonstrate that a recurrent USMG5 splice-site founder mutation in the Ashkenazi Jewish population causes autosomal recessive Leigh syndrome by reduction of CV dimerization and ATP synthesis.

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