2. Academic Validation
  3. Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder

Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder

  • Nat Genet. 2015 Aug;47(8):926-32. doi: 10.1038/ng.3354.
Alexander J Abrams 1,  Robert B Hufnagel 2,  Adriana Rebelo 3,  Claudia Zanna 4,  Neville Patel 5,  Michael A Gonzalez 3,  Ion J Campeanu 5,  Laurie B Griffin 6,  Saskia Groenewald 5,  Alleene V Strickland 3,  Feifei Tao 3,  Fiorella Speziani 3,  Lisa Abreu 3,  Rebecca Schüle 7,  Leonardo Caporali 8,  Chiara La Morgia 4,  Alessandra Maresca 4,  Rocco Liguori 4,  Raffaele Lodi 9,  Zubair M Ahmed 10,  Kristen L Sund 2,  Xinjian Wang 2,  Laura A Krueger 2,  Yanyan Peng 2,  Carlos E Prada 2,  Cynthia A Prows 2,  Elizabeth K Schorry 2,  Anthony Antonellis 11,  Holly H Zimmerman 12,  Omar A Abdul-Rahman 12,  Yaping Yang 13,  Susan M Downes 14,  Jeffery Prince 5,  Flavia Fontanesi 15,  Antonio Barrientos 16,  Andrea H Németh 17,  Valerio Carelli 4,  Taosheng Huang 2,  Stephan Zuchner 3,  Julia E Dallman 5
Affiliations

Affiliations

  • 1 1] John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA. [2] Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA. [3] Department of Biology, University of Miami, Coral Gables, Florida, USA.
  • 2 Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
  • 3 1] John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA. [2] Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA.
  • 4 1] Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, Bologna, Italy. [2] Neurology Unit, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
  • 5 Department of Biology, University of Miami, Coral Gables, Florida, USA.
  • 6 1] Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, USA. [2] Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, USA.
  • 7 1] John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA. [2] Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA. [3] Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. [4] German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  • 8 Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, Bologna, Italy.
  • 9 Policlinico S. Orsola-Malpighi Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
  • 10 Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
  • 11 1] Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA. [2] Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  • 12 Department of Pediatrics, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
  • 13 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • 14 1] Nuffield Department of Clinical Neuroscience, University of Oxford, John Radcliffe Hospital, Oxford, UK. [2] Oxford Eye Hospital National Health Service (NHS) Trust, Oxford, UK.
  • 15 Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida, USA.
  • 16 1] Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida, USA. [2] Department of Neurology, University of Miami, Miami, Florida, USA.
  • 17 1] Nuffield Department of Clinical Neuroscience, University of Oxford, John Radcliffe Hospital, Oxford, UK. [2] Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
PMID: 26168012 DOI: 10.1038/ng.3354
Abstract

Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.

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