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

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)

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).

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