Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS - like clinical syndrome

• DOI: 10.17863/cam.38987
• Publication Date: 2017-08-25
• Authors: Maria Alice Donati; Martino Montomoli; Cristina Dallabona; Pedro Rebelo-Guiomar; Pedro Rebelo-Guiomar; Tiziana Lodi; Caterina Garone; Caterina Garone; Renzo Guerrini; Vamsi K. Mootha; Sarah E. Calvo; Sarah E. Calvo; Michal Minczuk; Aaron R. D’Souza; Salvatore DiMauro; Elena Procopio; Massimo Zeviani; Joanna Rorbach; Ileana Ferrero
• Keywords: Male; 0301 basic medicine; 16S; 570; 610; Saccharomyces cerevisiae; DNA, Mitochondrial; Mitochondrial Encephalomyopathie; 03 medical and health sciences; Genetic; Mitochondrial Encephalomyopathies; RNA, Ribosomal, 16S; MELAS Syndrome; Humans; Amino Acid Sequence; Child; Methyltransferase; Molecular Biology; Genetics (clinical); Nuclear Protein; Ribosomal; Amino Acid Sequence; Child; DNA, Mitochondrial; Humans; MELAS Syndrome; Male; Methyltransferases; Mitochondria; Mitochondrial Encephalomyopathies; Mutation; Nuclear Proteins; RNA, Ribosomal; RNA, Ribosomal, 16S; Saccharomyces cerevisiae; Nuclear Proteins; DNA; Articles; Methyltransferases; mitochondrial; Mitochondrial; Mitochondria; 3. Good health; RNA, Ribosomal; Mutation; RNA; Human

Defects in nuclear-encoded proteins of the mitochondrial translation machinery cause early-onset and tissue-specific deficiency of one or more OXPHOS complexes. Here, we report a 7-year-old Italian boy with childhood-onset rapidly progressive encepha- lomyopathy and stroke-like episodes. Multiple OXPHOS defects and decreased mtDNA copy number (40%) were detected in muscle homogenate. Clinical features combined with low level of plasma citrulline were highly suggestive of mitochondrial en- cephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, however, the common m.3243 A > G mutation was ex- cluded. Targeted exome sequencing of genes encoding the mitochondrial proteome identified a damaging mutation, c.567 G > A, affecting a highly conserved amino acid residue (p.Gly189Arg) of the MRM2 protein. MRM2 has never before been linked to a hu- man disease and encodes an enzyme responsible for 2’-O-methyl modification at position U1369 in the human mitochondrial 16S rRNA. We generated a knockout yeast model for the orthologous gene that 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 com- pletely rescued by expressing the wild-type allele. Our findings establish that defective MRM2 causes a MELAS-like phenotype, and suggests the genetic screening of the MRM2 gene in patients with a m.3243 A > G negative MELAS-like presentation.