title: Novel insights into SLC25A46-related pathologies in a genetic mouse model.
abstract: The mitochondrial protein SLC25A46 has been recently identified as a novel pathogenic cause in a wide spectrum of neurological diseases, including inherited optic atrophy, Charcot-Marie-Tooth type 2, Leigh syndrome, progressive myoclonic ataxia and lethal congenital pontocerebellar hypoplasia. SLC25A46 is an outer membrane protein, member of the Solute Carrier 25 (SLC25) family of nuclear genes encoding mitochondrial carriers, with a role in mitochondrial dynamics and cristae maintenance. Here we identified a loss-of-function mutation in the Slc25a46 gene that causes lethal neuropathology in mice. Mutant mice manifest the main clinical features identified in patients, including ataxia, optic atrophy and cerebellar hypoplasia, which were completely rescued by expression of the human ortholog. Histopathological analysis revealed previously unseen lesions, most notably disrupted cytoarchitecture in the cerebellum and retina and prominent abnormalities in the neuromuscular junction. A distinct lymphoid phenotype was also evident. Our mutant mice provide a valid model for understanding the mechanistic basis of the complex SLC25A46-mediated pathologies, as well as for screening potential therapeutic interventions.
authors.affiliation: Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.|Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Maria Eirini
authors.initials: ME
authors.lastname: Terzenidou
authors.affiliation: Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Segklia
authors.affiliation: Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.|Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Kano
authors.affiliation: Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Florentia
authors.initials: F
authors.lastname: Papastefanaki
authors.affiliation: Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.|Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Karakostas
authors.affiliation: Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Maria
authors.identifier: 0000-0001-8417-1023
authors.initials: M
authors.lastname: Charalambous
authors.affiliation: Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.|Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Fotis
authors.initials: F
authors.lastname: Ioakeimidis
authors.affiliation: Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.|Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Papadaki
authors.affiliation: Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors.forename: Ismini
authors.initials: I
authors.lastname: Kloukina
authors.affiliation: Laboratory of Neurobiology, Histochemistry and Electron Microscopy, 1st Department of Psychiatry, University of Athens Medical School, Eginition Hospital, Athens, Greece.
authors.forename: Margarita
authors.initials: M
authors.lastname: Chrysanthou-Piterou
authors.affiliation: Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Martina
authors.initials: M
authors.lastname: Samiotaki
authors.affiliation: Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Panayotou
authors.affiliation: Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Matsas
authors.affiliation: Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.|Biomedical Sciences Research Center "Alexander Fleming", Vari, Greece.
authors.forename: Eleni
authors.identifier: 0000-0003-0004-5121
authors.initials: E
authors.lastname: Douni
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000503:physiopathology; D002526:Cerebellar Diseases / Q000235:genetics / Q000503:physiopathology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009896:Optic Atrophy / Q000235:genetics / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D028061:Phosphate Transport Proteins / Q000235:genetics*
chemical_list: D024101:Mitochondrial Proteins; D028061:Phosphate Transport Proteins; C584459:SLC25A46 protein, human