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

Debby M. E. I. Hellebrekers; Emma L. Blakely; Alexandra T. M. Hendrickx; Steven A. Hardy; Sila Hopton; Gavin Falkous; Irenaeus F. M. de Coo; Hubert J. M. Smeets; Nadine M. E. van der Beek; Robert W. Taylor

doi:10.1016/j.nmd.2019.08.005

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

Debby M. E. I. Hellebrekers^*, Emma L. Blakely, Alexandra T. M. Hendrickx, Steven A. Hardy, Sila Hopton, Gavin Falkous, Irenaeus F. M. de Coo, Hubert J. M. Smeets, Nadine M. E. van der Beek, Robert W. Taylor

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	693-697
Number of pages	5
Journal	Neuromuscular Disorders
Volume	29
Issue number	9
DOIs	https://doi.org/10.1016/j.nmd.2019.08.005
Publication status	Published - Sept 2019

Keywords

Mitochondrial disease
Chronic progressive external ophthalmoplegia
Myopathy
mtDNA variant
m.4414T>C
MTTM
MUTATION
ASSAY

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Cite this

Hellebrekers, D. M. E. I., Blakely, E. L., Hendrickx, A. T. M., Hardy, S. A., Hopton, S., Falkous, G., de Coo, I. F. M., Smeets, H. J. M., van der Beek, N. M. E., & Taylor, R. W. (2019). A novel mitochondrial m.4414T > C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy. Neuromuscular Disorders, 29(9), 693-697. https://doi.org/10.1016/j.nmd.2019.08.005

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

abstract = "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.",

keywords = "Mitochondrial disease, Chronic progressive external ophthalmoplegia, Myopathy, mtDNA variant, m.4414T>C, MTTM, MUTATION, ASSAY",

author = "Hellebrekers, {Debby M. E. I.} and Blakely, {Emma L.} and Hendrickx, {Alexandra T. M.} and Hardy, {Steven A.} and Sila Hopton and Gavin Falkous and {de Coo}, {Irenaeus F. M.} and Smeets, {Hubert J. M.} and {van der Beek}, {Nadine M. E.} and Taylor, {Robert W.}",

note = "Funding Information: RWT is supported by the Wellcome Centre for Mitochondrial Research ( 203105/Z/16/Z ), the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease, the Mitochondrial Disease Patient Cohort (UK) ( G0800674 ), the Lily Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, the MRC/EPSRC Molecular Pathology Node and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children ( http://www.newcastle-mitochondria.com/ ). IdC is funded by NeMO. Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = sep,

doi = "10.1016/j.nmd.2019.08.005",

language = "English",

volume = "29",

pages = "693--697",

journal = "Neuromuscular Disorders",

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T1 - A novel mitochondrial m.4414T > C MT-TM gene variant causing progressive external ophthalmoplegia and myopathy

AU - Hellebrekers, Debby M. E. I.

AU - Blakely, Emma L.

AU - Hendrickx, Alexandra T. M.

AU - Hardy, Steven A.

AU - Hopton, Sila

AU - Falkous, Gavin

AU - de Coo, Irenaeus F. M.

AU - Smeets, Hubert J. M.

AU - van der Beek, Nadine M. E.

AU - Taylor, Robert W.

N1 - Funding Information: RWT is supported by the Wellcome Centre for Mitochondrial Research ( 203105/Z/16/Z ), the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease, the Mitochondrial Disease Patient Cohort (UK) ( G0800674 ), the Lily Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, the MRC/EPSRC Molecular Pathology Node and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children ( http://www.newcastle-mitochondria.com/ ). IdC is funded by NeMO. Publisher Copyright: © 2019 The Author(s)

PY - 2019/9

Y1 - 2019/9

N2 - 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.

AB - 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.

KW - Mitochondrial disease

KW - Chronic progressive external ophthalmoplegia

KW - Myopathy

KW - mtDNA variant

KW - m.4414T>C

KW - MTTM

KW - MUTATION

KW - ASSAY

U2 - 10.1016/j.nmd.2019.08.005

DO - 10.1016/j.nmd.2019.08.005

M3 - Article

C2 - 31488384

SN - 0960-8966

VL - 29

SP - 693

EP - 697

JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

IS - 9

ER -