@article{discovery10089551,
            year = {2020},
          volume = {6},
          number = {1},
           title = {Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutations},
            note = {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.},
       publisher = {Ovid Technologies (Wolters Kluwer Health)},
           month = {February},
         journal = {Neurology Genetics},
        keywords = {All Genetics; Gait disorders/ataxia; Mitochondrial disorders; Metabolic disease (inherited);},
        abstract = {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{\ensuremath{>}}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{\ensuremath{>}}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.},
          author = {Bugiardini, E and Bottani, E and Marchet, S and Poole, OV and Beninca, C and Horga, A and Woodward, C and Lam, A and Hargreaves, I and Chalasani, A and Valerio, A and Lamantea, E and Venner, K and Holton, JL and Zeviani, M and Houlden, H and Quinlivan, R and Lamperti, C and Hanna, MG and Pitceathly, RDS},
             url = {https://doi.org/10.1212/NXG.0000000000000381}
}