title: A comparative analysis approach to determining the pathogenicity of mitochondrial tRNA mutations.
abstract: Distinguishing pathogenic from polymorphic changes poses significant problems for geneticists and despite 30 years of postgenomic experience this remains the case in mitochondrial genetics. Base substitutions in mitochondrial tRNA (mt-tRNA) genes are particularly difficult, but important, because they are common causes of pathology and associated with high rates of transmission. Providing accurate genetic advice to patients and their families is of paramount importance in disease prevention, and brings into sharp focus the factors used to distinguish pathogenic from polymorphic variants. We have reevaluated our pathogenicity scoring system for mt-tRNA mutations following a considerable increase in the number reported since the system was devised in 2004. This allowed us to address notable issues including the underestimation of "definitely pathogenic" mutations resulting from insufficient data collection. We illustrate the robustness of our revised scoring system using novel pathogenic and previously reported polymorphic changes and conclude that while clear evidence from single-fiber and/or trans-mitochondrial cybrid studies remains the gold standard for assigning pathogenicity, our scoring system is valuable for deciding which mt-tRNA mutations to investigate further using these labor-intensive techniques.
authors: Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, UK.
authors: John W
authors: JW
authors: Yarham
authors: Mazhor
authors: M
authors: Al-Dosary
authors: Emma L
authors: EL
authors: Blakely
authors: Charlotte L
authors: CL
authors: Alston
authors: Robert W
authors: RW
authors: Taylor
authors: Joanna L
authors: JL
authors: Elson
authors: Robert
authors: R
authors: McFarland
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D030541:Databases, Genetic; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D012313:RNA / Q000235:genetics*; D000077278:RNA, Mitochondrial; D012343:RNA, Transfer / Q000235:genetics*
chemical_list: D000077278:RNA, Mitochondrial; D012313:RNA; D012343:RNA, Transfer