%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.
%I Ovid Technologies (Wolters Kluwer Health)
%L discovery10089551
%J Neurology Genetics
%A E Bugiardini
%A E Bottani
%A S Marchet
%A OV Poole
%A C Beninca
%A A Horga
%A C Woodward
%A A Lam
%A I Hargreaves
%A A Chalasani
%A A Valerio
%A E Lamantea
%A K Venner
%A JL Holton
%A M Zeviani
%A H Houlden
%A R Quinlivan
%A C Lamperti
%A MG Hanna
%A RDS Pitceathly
%O 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.
%V 6
%D 2020
%K All Genetics; Gait disorders/ataxia; Mitochondrial disorders; Metabolic disease (inherited);
%T Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutations
%N 1