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

• DOI: 10.1038/ng.3354
• Publication Date: 2015-07-13T16:17:28Z
• Authors: 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
• Keywords: Male; 0301 basic medicine; Embryo, Nonmammalian; Muscle Proteins; IMMT protein, human; genetics [Muscle Proteins]; Medical and Health Sciences; pathology [Optic Atrophy, Autosomal Dominant]; Animals, Genetically Modified; metabolism [Optic Atrophy, Autosomal Dominant]; Charcot-Marie-Tooth Disease; genetics [Phosphate Transport Proteins]; Chlorocebus aethiops; genetics [Exome]; Phosphate Transport Proteins; Exome; metabolism [Zebrafish]; Dominant optic atrophy; DOA; xonal peripheral neuropathy; Charcot-Marie-Tooth type 2, CMT2; hereditary neurodegenerative disorder; genetics [Genetic Predisposition to Disease]; embryology [Embryo, Nonmammalian]; Zebrafish; Microscopy; Nonmammalian; Microscopy, Confocal; Biological Sciences; Pedigree; genetics [Membrane Proteins]; Embryo; Autosomal Dominant; Confocal; Neurological; COS Cells; Mitochondrial Membranes; genetics [Mitochondrial Proteins]; RNA Interference; Female; genetics [Charcot-Marie-Tooth Disease]; Sequence Analysis; Protein Binding; UGO1 protein, S cerevisiae; 570; metabolism [Embryo, Nonmammalian]; Saccharomyces cerevisiae Proteins; metabolism [Muscle Proteins]; genetics [Optic Atrophy, Autosomal Dominant]; 610; Genetically Modified; metabolism [Phosphate Transport Proteins]; Electron; ultrastructure [Embryo, Nonmammalian]; metabolism [Mitochondrial Proteins]; Mitochondrial Proteins; 03 medical and health sciences; Rare Diseases; Microscopy, Electron, Transmission; ddc:570; metabolism [Mitochondrial Membranes]; Optic Atrophy, Autosomal Dominant; Genetics; Transmission; Animals; Humans; Genetic Predisposition to Disease; Eye Disease and Disorders of Vision; genetics [Saccharomyces cerevisiae Proteins]; Neurosciences; Membrane Proteins; DNA; Sequence Analysis, DNA; metabolism [Saccharomyces cerevisiae Proteins]; Brain Disorders; Optic Atrophy; HEK293 Cells; metabolism [Charcot-Marie-Tooth Disease]; Mutation; embryology [Zebrafish]; metabolism [Membrane Proteins]; Developmental Biology; SLC25A46 protein, human

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.