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