Abstract

Confirming the pathogenicity of mitochondrial tRNA point mutations is one of the classical challenges in the field of mitochondrial medicine. In addition to genetic and functional studies, the evaluation of a genetic change using a pathogenicity scoring system is extremely useful to discriminate between disease-causing mutations from neutral polymorphisms. The pathogenicity scoring system is very robust for confirming pathogenicity, especially of mutations that show impaired activity in functional studies. However, mutations giving normal results using the same functional approaches are disregarded, and this compromises the power of the system to rule out pathogenicity. We propose to include a new criterion in the pathogenicity scoring systems regarding mutations which fail to show any mitochondrial defect in functional studies. To evaluate this proposal we characterized two mutations, m.8296A>G and m.8347A>G, in the mitochondrial tRNALys gene (MT-TK) using trans-mitochondrial cybrid analysis. m.8347A>G mutation severely impairs oxidative phosphorylation, suggesting that it is highly pathogenic. By contrast, the behavior of cybrids homoplasmic for the m.8296A>G mutation is similar to cybrids containing wild-type mitochondrial DNA (mtDNA). The results indicate that including not only positive but also negative outcomes of functional studies in the scoring system is critical for facilitating the diagnosis of this complex group of diseases.

Highlights

  • Mitochondria are the main source of cellular ATP through the activity of the oxidative phosphorylation (OXPHOS) system

  • We propose to include a new criterion in the pathogenicity scoring systems regarding mutations which fail to show any mitochondrial defect in functional studies

  • Using the scoring system proposed by Yarham et al the m.8296A>G mutation was classified as possibly pathogenic (10 points derived from: >1 report, heteroplasmy, conservation, segregation with disease, and histochemistry) while the m.8347A>G was classified as a neutral polymorphism (4 points derived from: heteroplasmy and segregation with disease) (Yarham et al 2011)

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Summary

Introduction

Mitochondria are the main source of cellular ATP through the activity of the oxidative phosphorylation (OXPHOS) system. OXPHOS system is composed of five different complexes embedded in the inner mitochondrial membrane (complexes I–V) and two small electron carriers, namely ubiquinone and cytochrome c. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc

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