Bugiardini, E; Bottani, E; Marchet, S; Poole, OV; Beninca, C; Horga, A; Woodward, C; ... Pitceathly, RDS; + view all Bugiardini, E; Bottani, E; Marchet, S; Poole, OV; Beninca, C; Horga, A; Woodward, C; Lam, A; Hargreaves, I; Chalasani, A; Valerio, A; Lamantea, E; Venner, K; Holton, JL; Zeviani, M; Houlden, H; Quinlivan, R; Lamperti, C; Hanna, MG; Pitceathly, RDS; - view fewer (2020) Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutations. Neurology Genetics , 6 (1) , Article e381. 10.1212/nxg.0000000000000381.

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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>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.

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