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Identification and functional characterization of a novel MTFMT mutation associated with selective vulnerability of the visual pathway and a mild neurological phenotype

Abstract

Mitochondrial protein synthesis is initiated by formylated tRNA-methionine, which requires the activity of MTFMT, a methionyl-tRNA formyltransferase. Mutations in MTFMT have been associated with Leigh syndrome, early-onset mitochondrial leukoencephalopathy, microcephaly, ataxia, and cardiomyopathy. We identified compound heterozygous MTFMT mutations in a patient with a mild neurological phenotype and late-onset progressive visual impairment. MRI studies documented a progressive and selective involvement of the retrochiasmatic visual pathway. MTFMT was undetectable by immunoblot analysis of patient fibroblasts, resulting in specific defects in mitochondrial protein synthesis and assembly of the oxidative phosphorylation complexes. This report expands the clinical and MRI phenotypes associated with MTFMT mutations, illustrating the complexity of genotype-phenotype relationships in mitochondrial translation disorders.

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Acknowledgements

We are grateful to the affected patient and her family. RLP is the recipient of a doctoral award from the Fonds de Recherche du Québec—Santé (FRQS) and has been supported by the Fondation Monaco. MT is a recipient of the postdoctoral fellowship from the Canadian Institute of Health Research (CIHR). This work was supported by the Canadian Foundation of Radiologists, the Care4Rare Canada Consortium (steering committee: Kym Boycott (lead; University of Ottawa), Alex MacKenzie (co-lead; University of Ottawa), Jacek Majewski (McGill University), Michael Brudno (University of Toronto), Dennis Bulman (University of Ottawa), and David Dyment (University of Ottawa)) and funded in part by Genome Canada, the Canadian Institutes of Health Research (CIHR), the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and the Children’s Hospital of Eastern Ontario Foundation and an operating grant from the CIHR (MT15460) to EAS.

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Correspondence to Eric A. Shoubridge.

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The Institutional Review Board of our institution approved the research study, and the subject reported here gave her consent to participate in the study.

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Supplementary Figure 1.

Fundus photographs showing the progressive atrophy of the left optic nerve (A) in 2010 and (B) at the last clinical follow up in 2014. (GIF 250 kb)

High Resolution Image (TIFF 32.7 kb)

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La Piana, R., Weraarpachai, W., Ospina, L.H. et al. Identification and functional characterization of a novel MTFMT mutation associated with selective vulnerability of the visual pathway and a mild neurological phenotype. Neurogenetics 18, 97–103 (2017). https://doi.org/10.1007/s10048-016-0506-0

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  • DOI: https://doi.org/10.1007/s10048-016-0506-0

Keywords

  • MTFMT
  • OXPHOS defects
  • Optic pathway
  • Leukoencephalopathy
  • Whole exome sequencing