Human molecular genetics · 2022
Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Zheng Wen-Qiang, Pedersen Signe Vandal, Thompson Kyle, Bellacchio Emanuele, French Courtney E, Munro Benjamin, Pearson Toni S, Vogt Julie, Diodato Daria, Diemer Tue, Ernst Anja, Horvath Rita, Chitre Manali, Ek Jakob, Wibrand Flemming, Grange Dorothy K, Raymond Lucy, Zhou Xiao-Long, Taylor Robert W, Ostergaard Elsebet
Аннотация
TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. In addition, we document seven novel TARS2 variants-one nonsense variant and six missense variants-that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modeling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.