Insights into the genotype‐phenotype correlation and molecular function of SLC25A46. Issue 12 (17th September 2018)

• Record Type: Journal Article
• Authors: Abrams, Alexander J.; Fontanesi, Flavia; Tan, Natalie B. L.; Buglo, Elena; Campeanu, Ion J.; Rebelo, Adriana P.; Kornberg, Andrew J.; Phelan, Dean G.; Stark, Zornitza; Zuchner, Stephan
• Is Part Of: Human mutation. Volume 39:Issue 12(2018)
• Page Start: 1995
• Page End: 2007
• Publication Date: 2018-09-17
• Subjects: Ataxia -- Mitochondria -- Optic atrophy -- SLC25A46; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23639
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: 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. Abstract : This study identifies a novel missense mutation in the SLC25A46 gene causing optic atrophy, peripheral neuropathy, ataxia, but not cerebellar atrophy. Stability of the SLC25A46 protein inversely correlates with disease severity. The patient's p.R257Q variant does not markedly destabilize the protein. Instead, it affects the SLC25A46 interaction with MIC60 involved in mitochondrial dynamics and cristae remodeling. These results provide further insight into the genotype‐phenotype correlation for mutations in the gene and may inform clinical prognosis of such patients.