A novel acceptor stem variant in mitochondrial tRNATyr impairs mitochondrial translation and is associated with a severe phenotype

Kimberly A. Kripps, Marisa W. Friederich, Ting Chen, Austin A. Larson, David M. Mirsky, Yue Wang, Kurenai Tanji, Kaz M. Knight, Lee Jun Wong, Johan L.K. Van Hove

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Genetic defects in mitochondrial DNA encoded tRNA genes impair mitochondrial translation with resultant defects in the mitochondrial respiratory chain and oxidative phosphorylation system. The phenotypic spectrum of disease seen in mitochondrial tRNA defects is variable and proving pathogenicity of new variants is challenging. Only three pathogenic variants have been described previously in the mitochondrial tRNATyr gene MT-TY, with the reported phenotypes consisting largely of adult onset myopathy and ptosis. We report a patient with a novel MT-TY acceptor stem variant m.5889A>G at high heteroplasmy in muscle, low in blood, and absent in the mother's blood. The phenotype consisted of a childhood-onset severe multi-system disorder characterized by a neurodegenerative course including ataxia and seizures, failure-to-thrive, combined myopathy and neuropathy, and hearing and vision loss. Brain imaging showed progressive atrophy and basal ganglia calcifications. Mitochondrial biomarkers lactate and GDF15 were increased. Functional studies showed a deficient activity of the respiratory chain enzyme complexes containing mtDNA-encoded subunits I, III and IV. There were decreased steady state levels of these mitochondrial complex proteins, and presence of incompletely assembled complex V forms in muscle. These changes are typical of a mitochondrial translational defect. These data support the pathogenicity of this novel variant. Careful review of variants in MT-TY additionally identified two other pathogenic variants, one likely pathogenic variant, nine variants of unknown significance, five likely benign and four benign variants.

Original languageEnglish (US)
Pages (from-to)398-404
Number of pages7
JournalMolecular Genetics and Metabolism
Issue number4
StatePublished - Dec 2020
Externally publishedYes


  • Mitochondrial tRNA
  • Mitochondrial translation disorder
  • Mt-tRNA
  • Multisystem mitochondrial disorder
  • Neurodegenerative disorder
  • Pathogenicity of mtDNA variants

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


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