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Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children

Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children
Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children
Background: The POLG1 gene encodes the catalytic
subunit of DNA polymerase gamma, essential for
mitochondrial DNA replication and repair. Mutations in
POLG1 have been linked to a spectrum of clinical
phenotypes, and may account for up to 25% of all adult
presentations of mitochondrial disease.
Methods and results: We present 14 patients, with
characteristic features of mitochondrial disease including
progressive external ophthalmoplegia (PEO) and Alpers–
Huttenlocher syndrome and laboratory findings indicative
of mitochondrial dysfunction, including cytochrome c
oxidase (COX) deficiency and multiple deletions or
depletion of the mitochondrial DNA. Four novel POLG1
missense substitutions (p.R597W, p.L605R, p.G746S,
p.A862T), are described, together with the first adult
patient with a recently described polymerase domain
mutation (p.R1047W). All novel changes were rare in a
control population and affected highly conserved amino
acids.
Conclusion: The addition of these substitutions—
including the first report of a dinucleotide mutation
(c.1814_1815TT.GC)—to the growing list of defects
further confirms the importance of POLG1 mutations as
the underlying abnormality in a range of neurological
presentations.
0022-2593
209-214
Stewart, J. D.
e1ec9784-39cc-48ed-9f4f-2a05d25f2106
Tennant, S.
6607a5ed-285e-471e-8b1c-10012ef5dce6
Powell, H.
3132d3db-f372-4c2c-b1a0-281d85153e35
Pyle, A.
5b0cf110-aef1-4797-bfbe-af9624c8e72e
Blakely, E. L.
5e68ada6-062d-435a-b49e-1a063c2589ab
He, L.
28f5c0e1-e0d6-4383-a10f-972815e0a7e4
Hudson, G.
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Roberts, M.
8841b432-f080-4b49-a9f4-1a1fbaed1a81
du Plessis, D.
e4bbac88-dac8-4130-b068-05ac671e0a5b
Gow, D.
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Mewasingh, L .D.
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Hanna, M. G.
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Omer, S.
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Morris, A. A.
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Roxburgh, R.
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Livingston, J. H.
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McFarland, R.
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Turnbull, D. M.
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Chinnery, P .F.
d76326aa-3be1-4c1e-8eb7-7ca967f009c9
Taylor, R .W.
8132031c-8091-4048-9faf-61e7a055f3f5
Stewart, J. D.
e1ec9784-39cc-48ed-9f4f-2a05d25f2106
Tennant, S.
6607a5ed-285e-471e-8b1c-10012ef5dce6
Powell, H.
3132d3db-f372-4c2c-b1a0-281d85153e35
Pyle, A.
5b0cf110-aef1-4797-bfbe-af9624c8e72e
Blakely, E. L.
5e68ada6-062d-435a-b49e-1a063c2589ab
He, L.
28f5c0e1-e0d6-4383-a10f-972815e0a7e4
Hudson, G.
27591c21-a00b-4dff-bea1-744c66e07e52
Roberts, M.
8841b432-f080-4b49-a9f4-1a1fbaed1a81
du Plessis, D.
e4bbac88-dac8-4130-b068-05ac671e0a5b
Gow, D.
2901cc4d-c029-41d4-a827-2aea5b2f6a63
Mewasingh, L .D.
d42b74ab-d5de-4d84-ada2-6da20b3bbef1
Hanna, M. G.
baf383d1-8982-48e9-b306-11583a93d00b
Omer, S.
d40ab8ff-6787-4967-891f-0e7c1bcbd900
Morris, A. A.
ea264a13-7a4a-45f6-a751-59c0306a2cdb
Roxburgh, R.
e6868bb7-7fcb-4c7d-baf4-e8b4869db0b2
Livingston, J. H.
7d7ab6f6-79e6-4caf-991a-0f7e17b5c48f
McFarland, R.
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Turnbull, D. M.
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Chinnery, P .F.
d76326aa-3be1-4c1e-8eb7-7ca967f009c9
Taylor, R .W.
8132031c-8091-4048-9faf-61e7a055f3f5

Stewart, J. D., Tennant, S., Powell, H., Pyle, A., Blakely, E. L., He, L., Hudson, G., Roberts, M., du Plessis, D., Gow, D., Mewasingh, L .D., Hanna, M. G., Omer, S., Morris, A. A., Roxburgh, R., Livingston, J. H., McFarland, R., Turnbull, D. M., Chinnery, P .F. and Taylor, R .W. (2009) Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children. Journal of Medical Genetics, 46, 209-214. (doi:10.1136/jmg.2008.058180). (PMID:19251978)

Record type: Article

Abstract

Background: The POLG1 gene encodes the catalytic
subunit of DNA polymerase gamma, essential for
mitochondrial DNA replication and repair. Mutations in
POLG1 have been linked to a spectrum of clinical
phenotypes, and may account for up to 25% of all adult
presentations of mitochondrial disease.
Methods and results: We present 14 patients, with
characteristic features of mitochondrial disease including
progressive external ophthalmoplegia (PEO) and Alpers–
Huttenlocher syndrome and laboratory findings indicative
of mitochondrial dysfunction, including cytochrome c
oxidase (COX) deficiency and multiple deletions or
depletion of the mitochondrial DNA. Four novel POLG1
missense substitutions (p.R597W, p.L605R, p.G746S,
p.A862T), are described, together with the first adult
patient with a recently described polymerase domain
mutation (p.R1047W). All novel changes were rare in a
control population and affected highly conserved amino
acids.
Conclusion: The addition of these substitutions—
including the first report of a dinucleotide mutation
(c.1814_1815TT.GC)—to the growing list of defects
further confirms the importance of POLG1 mutations as
the underlying abnormality in a range of neurological
presentations.

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Published date: 2009
Organisations: Centre for Biological Sciences

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Local EPrints ID: 355892
URI: http://eprints.soton.ac.uk/id/eprint/355892
ISSN: 0022-2593
PURE UUID: d98f8a25-e951-4974-9500-300cae7a6f13
ORCID for J. D. Stewart: ORCID iD orcid.org/0000-0002-2608-1967

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Date deposited: 04 Sep 2013 17:22
Last modified: 27 Oct 2023 03:13

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Contributors

Author: J. D. Stewart ORCID iD
Author: S. Tennant
Author: H. Powell
Author: A. Pyle
Author: E. L. Blakely
Author: L. He
Author: G. Hudson
Author: M. Roberts
Author: D. du Plessis
Author: D. Gow
Author: L .D. Mewasingh
Author: M. G. Hanna
Author: S. Omer
Author: A. A. Morris
Author: R. Roxburgh
Author: J. H. Livingston
Author: R. McFarland
Author: D. M. Turnbull
Author: P .F. Chinnery
Author: R .W. Taylor

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