TY - JOUR
T1 - A novel acceptor stem variant in mitochondrial tRNATyr impairs mitochondrial translation and is associated with a severe phenotype
AU - Kripps, Kimberly A.
AU - Friederich, Marisa W.
AU - Chen, Ting
AU - Larson, Austin A.
AU - Mirsky, David M.
AU - Wang, Yue
AU - Tanji, Kurenai
AU - Knight, Kaz M.
AU - Wong, Lee Jun
AU - Van Hove, Johan L.K.
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
KW - Mitochondrial tRNA
KW - Mitochondrial translation disorder
KW - Mt-tRNA
KW - Multisystem mitochondrial disorder
KW - Neurodegenerative disorder
KW - Pathogenicity of mtDNA variants
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U2 - 10.1016/j.ymgme.2020.11.006
DO - 10.1016/j.ymgme.2020.11.006
M3 - Article
C2 - 33279411
AN - SCOPUS:85097090032
SN - 1096-7192
VL - 131
SP - 398
EP - 404
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 4
ER -