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Pathogenic Mitochondrial tRNA Point Mutations: Nine Novel Mutations Affirm Their Importance as a Cause of Mitochondrial Disease

Lookup NU author(s): Dr John Yarham, Dr Charlotte Alston, Kate Craig, Dr Kirstie Anderson, Professor Doug Turnbull, Professor Bobby McFarland, Professor Robert Taylor

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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 counseling for patients and their families. The use of weighted criteria based on functional studiesoutlined in a validated pathogenicity scoring systemis therefore invaluable in determining whether novel or rare mt-tRNA variants are pathogenic. Here, we describe the identification of nine 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, isolated progressive external ophthalmoplegia, 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), whereas the remaining three currently lack sufficient evidence and are therefore classed as possibly pathogenic' (m.4289T>C, m.7554G>A, and m.8304G>A). (C) 2013 Wiley Periodicals, Inc.


Publication metadata

Author(s): Blakely EL, Yarham JW, Alston CL, Craig K, Poulton J, Brierley C, Park SM, Dean A, Xuereb JH, Anderson KN, Compston A, Allen C, Sharif S, Enevoldson P, Wilson M, Hammans SR, Turnbull DM, McFarland R, Taylor RW

Publication type: Article

Publication status: Published

Journal: Human Mutation

Year: 2013

Volume: 34

Issue: 9

Pages: 1260-1268

Print publication date: 14/08/2013

ISSN (print): 1059-7794

ISSN (electronic): 1098-1004

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/humu.22358

DOI: 10.1002/humu.22358


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