title: Pathogenic mitochondrial tRNA point mutations: nine novel mutations affirm their importance as a cause of mitochondrial disease.
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 studies-outlined in a validated pathogenicity scoring system--is 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).
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.forename: John W
authors.initials: JW
authors.lastname: Yarham
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.forename: Kate
authors.initials: K
authors.lastname: Craig
authors.forename: Joanna
authors.initials: J
authors.lastname: Poulton
authors.forename: Charlotte
authors.initials: C
authors.lastname: Brierley
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Park
authors.forename: Andrew
authors.initials: A
authors.lastname: Dean
authors.forename: John H
authors.initials: JH
authors.lastname: Xuereb
authors.forename: Kirstie N
authors.initials: KN
authors.lastname: Anderson
authors.forename: Alistair
authors.initials: A
authors.lastname: Compston
authors.forename: Chris
authors.initials: C
authors.lastname: Allen
authors.forename: Saba
authors.initials: S
authors.lastname: Sharif
authors.forename: Peter
authors.initials: P
authors.lastname: Enevoldson
authors.forename: Martin
authors.initials: M
authors.lastname: Wilson
authors.forename: Simon R
authors.initials: SR
authors.lastname: Hammans
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D017241:MELAS Syndrome / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics; D017354:Point Mutation; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D000077278:RNA, Mitochondrial; D012343:RNA, Transfer / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D000077278:RNA, Mitochondrial; D012313:RNA; D012343:RNA, Transfer
keywords: mitochondrial disease; mitochondrial tRNA; segregation; single-fiber studies