Novel insights into SLC25A46-related pathologies in a genetic mouse model.
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. SLC25...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-04-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC5380310?pdf=render |
| _version_ | 1818391227192573952 |
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| author | Maria Eirini Terzenidou Aikaterini Segklia Toshimi Kano Florentia Papastefanaki Alexandros Karakostas Maria Charalambous Fotis Ioakeimidis Maria Papadaki Ismini Kloukina Margarita Chrysanthou-Piterou Martina Samiotaki George Panayotou Rebecca Matsas Eleni Douni |
| author_facet | Maria Eirini Terzenidou Aikaterini Segklia Toshimi Kano Florentia Papastefanaki Alexandros Karakostas Maria Charalambous Fotis Ioakeimidis Maria Papadaki Ismini Kloukina Margarita Chrysanthou-Piterou Martina Samiotaki George Panayotou Rebecca Matsas Eleni Douni |
| author_sort | Maria Eirini Terzenidou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T05:10:10Z |
| format | Article |
| id | doaj.art-4155294d8c804fba86073e452f8f9a11 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-14T05:10:10Z |
| publishDate | 2017-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-4155294d8c804fba86073e452f8f9a112022-12-21T23:15:59ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-04-01134e100665610.1371/journal.pgen.1006656Novel insights into SLC25A46-related pathologies in a genetic mouse model.Maria Eirini TerzenidouAikaterini SegkliaToshimi KanoFlorentia PapastefanakiAlexandros KarakostasMaria CharalambousFotis IoakeimidisMaria PapadakiIsmini KloukinaMargarita Chrysanthou-PiterouMartina SamiotakiGeorge PanayotouRebecca MatsasEleni DouniThe 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.http://europepmc.org/articles/PMC5380310?pdf=render |
| spellingShingle | Maria Eirini Terzenidou Aikaterini Segklia Toshimi Kano Florentia Papastefanaki Alexandros Karakostas Maria Charalambous Fotis Ioakeimidis Maria Papadaki Ismini Kloukina Margarita Chrysanthou-Piterou Martina Samiotaki George Panayotou Rebecca Matsas Eleni Douni Novel insights into SLC25A46-related pathologies in a genetic mouse model. PLoS Genetics |
| title | Novel insights into SLC25A46-related pathologies in a genetic mouse model. |
| title_full | Novel insights into SLC25A46-related pathologies in a genetic mouse model. |
| title_fullStr | Novel insights into SLC25A46-related pathologies in a genetic mouse model. |
| title_full_unstemmed | Novel insights into SLC25A46-related pathologies in a genetic mouse model. |
| title_short | Novel insights into SLC25A46-related pathologies in a genetic mouse model. |
| title_sort | novel insights into slc25a46 related pathologies in a genetic mouse model |
| url | http://europepmc.org/articles/PMC5380310?pdf=render |
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