Evolution Meets Disease: Penetrance and Functional Epistasis of Mitochondrial tRNA Mutations

• DOI: 10.1371/journal.pgen.1001379
• Publication Date: 2011-04-21T20:47:23Z
• Authors: Raquel Moreno-Los...; Gustavo Ferrín; Rebeca Acín-Pérez; M. Esther Gallardo; Carlo Viscomi; Acisclo Pérez-Martos; Massimo Zeviani; Patricio Fernánde...; José Antonio Enrí...
• Keywords: Penetrance; Human mitochondrial genetics; Mitochondrial disease

About half of the mitochondrial DNA (mtDNA) mutations causing diseases in humans occur tRNA genes. Particularly intriguing are those pathogenic than can reach homoplasmy and yet show very different penetrance among patients. These scarce and, addition to their obvious interest for understanding human pathology, they be excellent experimental examples model evolution fixation mutations. To date, only source this type is We report here generation characterization first pathological mutation mouse cells, an m.3739G>A transition mt-Ti gene. This recapitulates molecular hallmarks a disease-causing described humans, m.4290T>C affecting also could determine that mechanism, induced by both mutations, high frequency abnormal folding tRNAIle cannot charged with isoleucine. demonstrate cells harboring or mutant have exacerbated biogenesis triggered increase ROS production as compensatory response. propose nature mechanism combined existence explain pattern mutation. particular behavior allow scenario tRNAs which two alleles individually deleterious proceed steps not require simultaneous both.