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A novel mitochondrial m.4414T>C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

Lookup NU author(s): Steven Hardy, Sila Hopton, Gavin Falkous, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2019 The Author(s)We report a novel mitochondrial m.4414T>C variant in the mt-tRNAMet (MT-TM) gene in an adult patient with chronic progressive external ophthalmoplegia and myopathy whose muscle biopsy revealed focal cytochrome c oxidase (COX)-deficient and ragged red fibres. The m.4414T>C variant occurs at a strongly evolutionary conserved sequence position, disturbing a canonical base pair and disrupting the secondary and tertiary structure of the mt-tRNAMet. Definitive evidence of pathogenicity is provided by clear segregation of m.4414T>C mutant levels with COX deficiency in single muscle fibres. Interestingly, the variant is present in skeletal muscle at relatively low levels (30%) and undetectable in accessible, non-muscle tissues from the patient and her asymptomatic brother, emphasizing the continuing requirement for a diagnostic muscle biopsy as the preferred tissue for mtDNA genetic investigations of mt-tRNA variants leading to mitochondrial myopathy.

Publication metadata

Author(s): Hellebrekers DMEI, Blakely EL, Hendrickx ATM, Hardy SA, Hopton S, Falkous G, de Coo IFM, Smeets HJM, van der Beek NME, Taylor RW

Publication type: Article

Publication status: Published

Journal: Neuromuscular Disorders

Year: 2019

Volume: 29

Issue: 9

Pages: 693-697

Print publication date: 01/09/2019

Online publication date: 21/08/2019

Acceptance date: 15/08/2019

Date deposited: 16/09/2019

ISSN (print): 0960-8966

ISSN (electronic): 1873-2364

Publisher: Elsevier Ltd


DOI: 10.1016/j.nmd.2019.08.005

PubMed id: 31488384


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