%0 Journal Article %A Bugiardini, E %A Bottani, E %A Marchet, S %A Poole, OV %A Beninca, C %A Horga, A %A Woodward, C %A Lam, A %A Hargreaves, I %A Chalasani, A %A Valerio, A %A Lamantea, E %A Venner, K %A Holton, JL %A Zeviani, M %A Houlden, H %A Quinlivan, R %A Lamperti, C %A Hanna, MG %A Pitceathly, RDS %D 2020 %F discovery:10089551 %I Ovid Technologies (Wolters Kluwer Health) %J Neurology Genetics %K All Genetics; Gait disorders/ataxia; Mitochondrial disorders; Metabolic disease (inherited); %N 1 %T Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutations %U https://discovery.ucl.ac.uk/id/eprint/10089551/ %V 6 %X OBJECTIVE: To describe the clinical and functional consequences of 1 novel and 1 previously reported truncating MT-ATP6 mutation. METHODS: Three unrelated probands with mitochondrial encephalomyopathy harboring truncating MT-ATP6 mutations are reported. Transmitochondrial cybrid cell studies were used to confirm pathogenicity of 1 novel variant, and the effects of all 3 mutations on ATPase 6 and complex V structure and function were investigated. RESULTS: Patient 1 presented with adult-onset cerebellar ataxia, chronic kidney disease, and diabetes, whereas patient 2 had myoclonic epilepsy and cerebellar ataxia; both harbored the novel m.8782G>A; p.(Gly86*) mutation. Patient 3 exhibited cognitive decline, with posterior white matter abnormalities on brain MRI, and severely impaired renal function requiring transplantation. The m.8618dup; p.(Thr33Hisfs*32) mutation, previously associated with neurogenic muscle weakness, ataxia, and retinitis pigmentosa, was identified. All 3 probands demonstrated a broad range of heteroplasmy across different tissue types. Blue-native gel electrophoresis of cultured fibroblasts and skeletal muscle tissue confirmed multiple bands, suggestive of impaired complex V assembly. Microscale oxygraphy showed reduced basal respiration and adenosine triphosphate synthesis, while reactive oxygen species generation was increased. Transmitochondrial cybrid cell lines studies confirmed the deleterious effects of the novel m.8782 G>A; p.(Gly86*) mutation. CONCLUSIONS: We expand the clinical and molecular spectrum of MT-ATP6-related mitochondrial disorders to include leukodystrophy, renal disease, and myoclonic epilepsy with cerebellar ataxia. Truncating MT-ATP6 mutations may exhibit highly variable mutant levels across different tissue types, an important consideration during genetic counseling. %Z This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.