期刊
NEUROMUSCULAR DISORDERS
卷 29, 期 9, 页码 693-697出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.nmd.2019.08.005
关键词
Mitochondrial disease; Chronic progressive external ophthalmoplegia; Myopathy; mtDNA variant; m.4414T > C; MTTM
资金
- Wellcome Centre for Mitochondrial Research [203105/Z/16/Z]
- Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease
- Mitochondrial Disease Patient Cohort (UK) [G0800674]
- Lily Foundation
- UK NIHR Biomedical Research Centre for Ageing and Age-related disease award
- MRC/EPSRC Molecular Pathology Node
- UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children
- NeMO
- MRC [G0800674, MR/L016354/1] Funding Source: UKRI
We report a novel mitochondrial m.4414T>C variant in the mt-tRNA(Met) (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-tRNA(Met). 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. (C) 2019 The Author(s). Published by Elsevier B.V.
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