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Pathogenic mitochondrial tRNA point mutations: nine novel mutations affirm their importance as a cause of mitochondrial disease

Pathogenic mitochondrial tRNA point mutations: nine novel mutations affirm their importance as a cause of mitochondrial disease
Pathogenic mitochondrial tRNA point mutations: nine novel mutations affirm their importance as a cause of mitochondrial disease
Mutations in the mitochondrial genome, and in particular the mt-tRNAs, are an important cause of human disease. Accurate classification of the pathogenicity of novel variants is vital to allow accurate genetic counselling for patients and their families. The use of weighted criteria based on functional studies - outlined in a validated pathogenicity scoring system - are therefore invaluable in determining whether novel or rare mt-tRNA variants are pathogenic. Here we describe the identification of 9 novel mt-tRNA variants in nine families, in which the probands presented with a diverse range of clinical phenotypes including mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), isolated progressive external ophthalmoplegia (PEO), epilepsy, deafness and diabetes. Each of the variants identified (m.4289T>C, MT-TI; m.5541C>T, MT-TW; m.5690A>G, MT-TN; m.7451A>T, MT-TS1; m.7554G>A, MT-TD; m.8304G>A, MT-TK; m.12206C>T, MT-TH; m.12317T>C, MT-TL2; m.16023G>A, MT-TP) was present in a different tRNA, with evidence in support of pathogenicity, and where possible, details of mutation transmission documented. Through the application of the pathogenicity scoring system, we have classified six of these variants as 'definitely pathogenic' mutations (m.5541C>T, m.5690A>G, m.7451A>T, m.12206C>T, m.12317T>C and m.16023G>A), whilst the remaining three currently lack sufficient evidence and are therefore classed as 'possibly pathogenic'(m.4289T>C, m.7554G>A and m.8304G>A). This article is protected by copyright. All rights reserved.
1059-7794
1260-1268
Blakely, Emma L.
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Yarham, John W.
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Alston, Charlotte L.
072f5616-ae09-416d-8818-411fc2057234
Craig, Kate
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Poulton, Joanna
cddc91cb-c16c-4e53-955e-bb79e85b450a
Brierley, Charlotte
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Park, Soo-Mi
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Dean, Andrew
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Xuereb, John H.
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Anderson, Kirstie N.
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Compston, Alistair
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Allen, Chris
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Sharif, Saba
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Enevoldson, Peter
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Wilson, Martin
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Hammans, Simon R.
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Turnbull, Douglass M.
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McFarland, Robert
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Taylor, Robert W.
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Blakely, Emma L.
9fc59eb0-626a-43f3-bc34-db5adca3fa04
Yarham, John W.
82736e6e-c57f-41c3-8656-41c1d004b7d6
Alston, Charlotte L.
072f5616-ae09-416d-8818-411fc2057234
Craig, Kate
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Poulton, Joanna
cddc91cb-c16c-4e53-955e-bb79e85b450a
Brierley, Charlotte
9343e977-d35a-4591-9529-c779bca77288
Park, Soo-Mi
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Dean, Andrew
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Xuereb, John H.
a2fb72d9-aecf-492a-bbfb-dbe506cda5c8
Anderson, Kirstie N.
4043dac6-0a5c-496c-bcdb-b781d3492b27
Compston, Alistair
d249582d-d2b1-4358-b394-422409e8533d
Allen, Chris
fe643d61-fa8e-4237-a557-1657b9ea6855
Sharif, Saba
9e976d1f-c6b2-4278-a2ea-40cc813269ad
Enevoldson, Peter
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Wilson, Martin
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Hammans, Simon R.
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Turnbull, Douglass M.
3fea24ec-1346-4c46-8aa0-02fac4bdec6a
McFarland, Robert
b3974785-4a44-4628-82d7-8e5b8661207c
Taylor, Robert W.
094ef050-e4ce-4394-a68f-35b58255104d

Blakely, Emma L., Yarham, John W., Alston, Charlotte L., Craig, Kate, Poulton, Joanna, Brierley, Charlotte, Park, Soo-Mi, Dean, Andrew, Xuereb, John H., Anderson, Kirstie N., Compston, Alistair, Allen, Chris, Sharif, Saba, Enevoldson, Peter, Wilson, Martin, Hammans, Simon R., Turnbull, Douglass M., McFarland, Robert and Taylor, Robert W. (2013) Pathogenic mitochondrial tRNA point mutations: nine novel mutations affirm their importance as a cause of mitochondrial disease. Human Mutation, 34 (9), 1260-1268. (doi:10.1002/humu.22358). (PMID:23696415)

Record type: Article

Abstract

Mutations in the mitochondrial genome, and in particular the mt-tRNAs, are an important cause of human disease. Accurate classification of the pathogenicity of novel variants is vital to allow accurate genetic counselling for patients and their families. The use of weighted criteria based on functional studies - outlined in a validated pathogenicity scoring system - are therefore invaluable in determining whether novel or rare mt-tRNA variants are pathogenic. Here we describe the identification of 9 novel mt-tRNA variants in nine families, in which the probands presented with a diverse range of clinical phenotypes including mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), isolated progressive external ophthalmoplegia (PEO), epilepsy, deafness and diabetes. Each of the variants identified (m.4289T>C, MT-TI; m.5541C>T, MT-TW; m.5690A>G, MT-TN; m.7451A>T, MT-TS1; m.7554G>A, MT-TD; m.8304G>A, MT-TK; m.12206C>T, MT-TH; m.12317T>C, MT-TL2; m.16023G>A, MT-TP) was present in a different tRNA, with evidence in support of pathogenicity, and where possible, details of mutation transmission documented. Through the application of the pathogenicity scoring system, we have classified six of these variants as 'definitely pathogenic' mutations (m.5541C>T, m.5690A>G, m.7451A>T, m.12206C>T, m.12317T>C and m.16023G>A), whilst the remaining three currently lack sufficient evidence and are therefore classed as 'possibly pathogenic'(m.4289T>C, m.7554G>A and m.8304G>A). This article is protected by copyright. All rights reserved.

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e-pub ahead of print date: 20 May 2013
Published date: September 2013
Organisations: Human Development & Health

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Local EPrints ID: 353022
URI: https://eprints.soton.ac.uk/id/eprint/353022
ISSN: 1059-7794
PURE UUID: 104865de-2310-451c-8a21-e6ee6f9a34f7

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Date deposited: 28 May 2013 13:06
Last modified: 16 Jul 2019 21:32

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Contributors

Author: Emma L. Blakely
Author: John W. Yarham
Author: Charlotte L. Alston
Author: Kate Craig
Author: Joanna Poulton
Author: Charlotte Brierley
Author: Soo-Mi Park
Author: Andrew Dean
Author: John H. Xuereb
Author: Kirstie N. Anderson
Author: Alistair Compston
Author: Chris Allen
Author: Saba Sharif
Author: Peter Enevoldson
Author: Martin Wilson
Author: Simon R. Hammans
Author: Douglass M. Turnbull
Author: Robert McFarland
Author: Robert W. Taylor

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