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

Alexander J Abrams; Robert B Hufnagel; Adriana Rebelo; Claudia Zanna; Neville Patel; Michael A Gonzalez; Ion J Campeanu; Laurie B Griffin; Saskia Groenewald; Alleene V Strickland; Feifei Tao; Fiorella Speziani; Lisa Abreu; Rebecca Schüle; Leonardo Caporali; Chiara La Morgia; Alessandra Maresca; Rocco Liguori; Raffaele Lodi; Zubair M Ahmed; Kristen L Sund; Xinjian Wang; Laura A Krueger; Yanyan Peng; Carlos E Prada; Cynthia A Prows; Elizabeth K Schorry; Anthony Antonellis; Holly H Zimmerman; Omar A Abdul-Rahman; Yaping Yang; Susan M Downes; Jeffery Prince; Flavia Fontanesi; Antonio Barrientos; Andrea H Németh; Valerio Carelli; Taosheng Huang; Stephan Zuchner; Julia E Dallman

doi:10.1038/ng.3354

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. Epub 2015 Jul 13.

Authors

Alexander J Abrams¹, Robert B Hufnagel², Adriana Rebelo³, Claudia Zanna⁴, Neville Patel⁵, Michael A Gonzalez³, Ion J Campeanu⁵, Laurie B Griffin⁶, Saskia Groenewald⁵, Alleene V Strickland³, Feifei Tao³, Fiorella Speziani³, Lisa Abreu³, Rebecca Schüle⁷, Leonardo Caporali⁸, Chiara La Morgia⁴, Alessandra Maresca⁴, Rocco Liguori⁴, Raffaele Lodi⁹, Zubair M Ahmed¹⁰, Kristen L Sund², Xinjian Wang², Laura A Krueger², Yanyan Peng², Carlos E Prada², Cynthia A Prows², Elizabeth K Schorry², Anthony Antonellis¹¹, Holly H Zimmerman¹², Omar A Abdul-Rahman¹², Yaping Yang¹³, Susan M Downes¹⁴, Jeffery Prince⁵, Flavia Fontanesi¹⁵, Antonio Barrientos¹⁶, Andrea H Németh¹⁷, Valerio Carelli⁴, Taosheng Huang², Stephan Zuchner³, Julia E Dallman⁵

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
PMCID: PMC4520737
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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Genetically Modified
COS Cells
Charcot-Marie-Tooth Disease / genetics
Charcot-Marie-Tooth Disease / metabolism
Chlorocebus aethiops
Embryo, Nonmammalian / embryology
Embryo, Nonmammalian / metabolism
Embryo, Nonmammalian / ultrastructure
Exome / genetics
Female
Genetic Predisposition to Disease / genetics*
HEK293 Cells
Humans
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Microscopy, Confocal
Microscopy, Electron, Transmission
Mitochondrial Membranes / metabolism
Mitochondrial Proteins / genetics*
Mitochondrial Proteins / metabolism
Muscle Proteins / genetics
Muscle Proteins / metabolism
Mutation*
Optic Atrophy, Autosomal Dominant / genetics*
Optic Atrophy, Autosomal Dominant / metabolism
Optic Atrophy, Autosomal Dominant / pathology
Pedigree
Phosphate Transport Proteins / genetics*
Phosphate Transport Proteins / metabolism
Protein Binding
RNA Interference
Saccharomyces cerevisiae Proteins / genetics
Saccharomyces cerevisiae Proteins / metabolism
Sequence Analysis, DNA
Zebrafish / embryology
Zebrafish / metabolism

Substances

IMMT protein, human
Membrane Proteins
Mitochondrial Proteins
Muscle Proteins
Phosphate Transport Proteins
SLC25A46 protein, human
Saccharomyces cerevisiae Proteins
UGO1 protein, S cerevisiae

Abstract

Publication types

MeSH terms

Substances

Grants and funding