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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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

@article{b792aed04fd94bf189c138a376a3dee3,

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",

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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 -

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

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Keywords

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