Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome (P1.301)

Objective: NA Background: Autosomal recessive or X-linked mutations in nuclear genes encoding proteins of the mitochondrial translation machinery cause early-onset and tissue-specific multiple OXPHOS deficiencies, or predominant cytochrome oxidase deficiency, with variable clinical presentations. Design/Methods: NA Results: Here, we present a 7-year-old Italian boy with childhood-onset rapidly progressive encephalomyopathy and stroke-like episodes, leading to early death. Multiple OXPHOS defects and borderline low levels of mtDNA copy number (40%) were detected in muscle homogenate, and citrulline was low in plasma. These findings, and the clinical features, suggested the diagnosis of MELAS syndrome but the common m.3243Au003eG mtDNA mutation was excluded. By using next generation exome sequencing on a library containing the entire mitochondrial DNA and nuclear encoded mitochondrial genes we identified a damaging mutation, c.567Gu003eA, affecting a highly conserved aminoacid residue of the MRM2 protein (p.Gly189Arg). Our previously published data have shown that MRM2 introduces 2′-O-methyl modification at position U1369 in human mitochondrial 16S rRNA. In order to demonstrate the pathogenicity of the mutation, we generated a knockout yeast model for the orthologous gene, MRM2. mrm2Δ showed a defect in respiration and the reduction of the 2′-O-methyl modification at the equivalent position (U2791) in the yeast mitochondrial 21S rRNA. Complementation with the mrm2 allele carrying the equivalent yeast mutation failed to rescue the respiratory phenotype, which was instead completely rescued by expressing the wildtype allele. Conclusions: Our findings establish that defective MRM2 causes a MELAS-like phenotype, further expanding the clinical and genetic heterogeneity associated with defects of mtDNA metabolism. In addition, our discovery suggests that genetic screening of the MRM2 gene should be carried out in patients with a 3243-negative MELAS-like presentation. Disclosure: Dr. Garone has nothing to disclose. Dr. D’Souza has nothing to disclose. Dr. Dallabona has nothing to disclose. Dr. Lodi has nothing to disclose. Dr. Rebelo-Guiomar has nothing to disclose. Dr. Rorbach has nothing to disclose. Dr. Donati has nothing to disclose. Dr. Procopio has nothing to disclose. Dr. Montomoli has nothing to disclose. Dr. Guerrini has nothing to disclose. Dr. Zeviani has nothing to disclose. Dr. Calvo has nothing to disclose. Dr. Mootha has nothing to disclose. Dr. DiMauro has nothing to disclose. Dr. Ferrero has nothing to disclose. Dr. Minczuk has nothing to disclose.