Trends in Genetics
Genome AnalysisAssigning pathogenicity to mitochondrial tRNA mutations: when ‘definitely maybe’ is not good enough
Section snippets
mt-tRNA mutations
In total, 91 different mt-tRNA mutations were listed as pathogenic on MITOMAP, but 66 (73%) of these were listed as ‘provisional’. The pathogenic status of four mutations was listed as ‘unclear,’ whereas another four mutations were not clearly described as either pathogenic or polymorphic. A dual entry on both the list of pathogenic mutations and the list of polymorphic variants occurred on six occasions, whereas two mutations that were provisionally identified as pathogenic also have a
Unsubstantiated claims
Although the canonical criteria of DiMauro and Schon are now generally accepted, they have been neither rigorously nor uniformly applied to suspected novel pathogenic mt-tRNA mutations before publication. Several mt-tRNA mutations were reported before the precepts of the canonical criteria were conceived but others, published more recently, simply lack the required evidence. In our study, 26% of the ‘pathogenic’ mt-tRNA mutations listed on MITOMAP fulfilled three or fewer basic criteria that
Concluding remarks
Our analysis of the published mt-tRNA mutations listed on MITOMAP indicates that, at present, there is insufficient evidence to classify a large proportion of the reported mutations as pathogenic. Furthermore, through our analysis we have been able to arrive at the following conclusions: (i) ∼73% of pathogenic mutations occur in the stems of mt-tRNA secondary structure; (ii) ‘hotspots’ for pathogenic mutations occur in both the acceptor and anticodon stems; (iii) the disruption of Watson–Crick
Acknowledgements
The research reported here was supported in part by the Wellcome Trust (D.M.T), The Newcastle upon Tyne Hospitals NHS Trust (R.W.T) and the National Science Foundation (N.H). R.M. and J.L.E. are supported by an MRC (UK) Clinician Scientist Fellowship and an MRC (UK) Bioinformatics Training Fellowship, respectively.
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