eprintid: 10089551 rev_number: 34 eprint_status: archive userid: 608 dir: disk0/10/08/95/51 datestamp: 2020-01-16 14:55:13 lastmod: 2021-11-02 23:35:51 status_changed: 2020-01-16 14:55:13 type: article metadata_visibility: show creators_name: Bugiardini, E creators_name: Bottani, E creators_name: Marchet, S creators_name: Poole, OV creators_name: Beninca, C creators_name: Horga, A creators_name: Woodward, C creators_name: Lam, A creators_name: Hargreaves, I creators_name: Chalasani, A creators_name: Valerio, A creators_name: Lamantea, E creators_name: Venner, K creators_name: Holton, JL creators_name: Zeviani, M creators_name: Houlden, H creators_name: Quinlivan, R creators_name: Lamperti, C creators_name: Hanna, MG creators_name: Pitceathly, RDS title: Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutations ispublished: pub subjects: GOSH subjects: UCH divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F85 keywords: All Genetics; Gait disorders/ataxia; Mitochondrial disorders; Metabolic disease (inherited); 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. 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. date: 2020-02 date_type: published publisher: Ovid Technologies (Wolters Kluwer Health) official_url: https://doi.org/10.1212/NXG.0000000000000381 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1739755 doi: 10.1212/nxg.0000000000000381 lyricists_name: Bugiardini, Enrico lyricists_name: Hanna, Michael lyricists_name: Holton, Janice lyricists_name: Houlden, Henry lyricists_name: Lam, Amanda lyricists_name: Pitceathly, Robert lyricists_name: Quinlivan, Rosaline lyricists_id: EBUGI08 lyricists_id: MGHAN52 lyricists_id: JHOLT26 lyricists_id: HJHOU44 lyricists_id: AAJLA69 lyricists_id: RDSPI25 lyricists_id: RCMQU67 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Neurology Genetics volume: 6 number: 1 article_number: e381 citation: 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 <https://doi.org/10.1212/nxg.0000000000000381>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10089551/1/e381.full.pdf