Novel insights into SLC25A46-related pathologies in a genetic mouse model

PLoS Genet. 2017 Apr 4;13(4):e1006656. doi: 10.1371/journal.pgen.1006656. eCollection 2017 Apr.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia / genetics
  • Ataxia / physiopathology
  • Cerebellar Diseases / genetics
  • Cerebellar Diseases / physiopathology
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / pathology
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Knockout
  • Mitochondria / genetics*
  • Mitochondria / pathology
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / genetics*
  • Mutation / genetics*
  • Optic Atrophy / genetics
  • Optic Atrophy / physiopathology
  • Pedigree
  • Phenotype
  • Phosphate Transport Proteins / genetics*


  • Mitochondrial Proteins
  • Phosphate Transport Proteins
  • SLC25A46 protein, human

Supplementary concepts

  • Pontocerebellar Hypoplasia

Grant support

This research was partially financed by the European Union (European Social Fund-ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) Research Funding Programs THALIS-UOC "Mitochondrial dysfunction in neurodegenerative diseases" (grant code 377226) to RM and ED, ARISTEIA II Grant "DnaJmito" (grant code 4676) to ED and the Hellenic General Secretariat for Research and Technology Grant SYNERGASIA Noiseplus 09SΥΝ-21-969 to RM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.