title: The m.3291T>C mt-tRNA(Leu(UUR)) mutation is definitely pathogenic and causes multisystem mitochondrial disease.
abstract: Mitochondrial tRNA point mutations are important causes of human disease, and have been associated with a diverse range of clinical phenotypes. Definitively proving the pathogenicity of any given mt-tRNA mutation requires combined molecular, genetic and functional studies. Subsequent evaluation of the mutation using a pathogenicity scoring system is often very helpful in concluding whether or not the mutation is causing disease. Despite several independent reports linking the m.3291T>C mutation to disease in humans, albeit in association with several different phenotypes, its pathogenicity remains controversial. A lack of conclusive functional evidence and an over-emphasis on the poor evolutionary conservation of the affected nucleotide have contributed to this controversy. Here we describe an adult patient who presented with deafness and lipomas and evidence of mitochondrial abnormalities in his muscle biopsy, who harbours the m.3291T>C mutation, providing conclusive evidence of pathogenicity through analysis of mutation segregation with cytochrome c oxidase (COX) deficiency in single muscle fibres, underlining the importance of performing functional studies when assessing pathogenicity.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: John W
authors.initials: JW
authors.lastname: Yarham
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.forename: Mark E
authors.initials: ME
authors.lastname: Roberts
authors.forename: John
authors.initials: J
authors.lastname: Ealing
authors.forename: Piyali
authors.initials: P
authors.lastname: Pal
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: D001483:Base Sequence; D006801:Humans; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics*; D008969:Molecular Sequence Data; D017354:Point Mutation / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D000077278:RNA, Mitochondrial; D012356:RNA, Transfer, Leu / Q000235:genetics*
chemical_list: D000077278:RNA, Mitochondrial; D012356:RNA, Transfer, Leu; D012313:RNA