title: Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder.
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.
authors.affiliation: 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.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Abrams
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Hufnagel
authors.affiliation: 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.
authors.forename: Adriana
authors.initials: A
authors.lastname: Rebelo
authors.affiliation: 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.
authors.forename: Claudia
authors.initials: C
authors.lastname: Zanna
authors.affiliation: Department of Biology, University of Miami, Coral Gables, Florida, USA.
authors.forename: Neville
authors.initials: N
authors.lastname: Patel
authors.affiliation: 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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.affiliation: Department of Biology, University of Miami, Coral Gables, Florida, USA.
authors.forename: Ion J
authors.initials: IJ
authors.lastname: Campeanu
authors.affiliation: 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.
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Griffin
authors.affiliation: Department of Biology, University of Miami, Coral Gables, Florida, USA.
authors.forename: Saskia
authors.initials: S
authors.lastname: Groenewald
authors.affiliation: 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.
authors.forename: Alleene V
authors.initials: AV
authors.lastname: Strickland
authors.affiliation: 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.
authors.forename: Feifei
authors.initials: F
authors.lastname: Tao
authors.affiliation: 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.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Speziani
authors.affiliation: 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.
authors.forename: Lisa
authors.initials: L
authors.lastname: Abreu
authors.affiliation: 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.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, Bologna, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Caporali
authors.affiliation: 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.
authors.forename: Chiara
authors.initials: C
authors.lastname: La Morgia
authors.affiliation: 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.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Maresca
authors.affiliation: 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.
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.affiliation: Policlinico S. Orsola-Malpighi Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Lodi
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Sund
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Krueger
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Prada
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Prows
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Schorry
authors.affiliation: 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.
authors.forename: Anthony
authors.initials: A
authors.lastname: Antonellis
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Holly H
authors.initials: HH
authors.lastname: Zimmerman
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Abdul-Rahman
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Downes
authors.affiliation: Department of Biology, University of Miami, Coral Gables, Florida, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Prince
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida, USA.
authors.forename: Flavia
authors.initials: F
authors.lastname: Fontanesi
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida, USA. [2] Department of Neurology, University of Miami, Miami, Florida, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Barrientos
authors.affiliation: 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.
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Németh
authors.affiliation: 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.
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: Department of Biology, University of Miami, Coral Gables, Florida, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Dallman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019556:COS Cells; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D028061:Phosphate Transport Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism
chemical_list: C088548:IMMT protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D028061:Phosphate Transport Proteins; C584459:SLC25A46 protein, human; D029701:Saccharomyces cerevisiae Proteins; C423986:UGO1 protein, S cerevisiae