Insights into the genotype-phenotype correlation and molecular function of SLC25A46

Alexander J. Abrams, Flavia Fontanesi, Natalie B.L. Tan, Elena Buglo, Ion J. Campeanu, Adriana P. Rebelo, Andrew J. Kornberg, Dean G. Phelan, Zornitza Stark, Stephan Zuchner

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Recessive SLC25A46 mutations cause a spectrum of neurodegenerative disorders with optic atrophy as a core feature. We report a patient with optic atrophy, peripheral neuropathy, ataxia, but not cerebellar atrophy, who is on the mildest end of the phenotypic spectrum. By studying seven different nontruncating mutations, we found that the stability of the SLC25A46 protein inversely correlates with the severity of the disease and the patient's variant does not markedly destabilize the protein. SLC25A46 belongs to the mitochondrial transporter family, but it is not known to have transport function. Apart from this possible function, SLC25A46 forms molecular complexes with proteins involved in mitochondrial dynamics and cristae remodeling. We demonstrate that the patient's mutation directly affects the SLC25A46 interaction with MIC60. Furthermore, we mapped all of the reported substitutions in the protein onto a 3D model and found that half of them fall outside of the signature carrier motifs associated with transport function. We thus suggest that there are two distinct molecular mechanisms in SLC25A46-associated pathogenesis, one that destabilizes the protein while the other alters the molecular interactions of the protein. These results have the potential to inform clinical prognosis of such patients and indicate a pathway to drug target development.

Original languageEnglish (US)
Pages (from-to)1995-2007
Number of pages13
JournalHuman mutation
Issue number12
StatePublished - Dec 2018


  • Ataxia
  • Mitochondria
  • Optic atrophy
  • SLC25A46

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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