Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome.

Hum Mol Genet
Authors
Keywords
Abstract

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 encephalomyopathy 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 encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, however, the common m.3243 A > G mutation was excluded. 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 human 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 completely 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.

Year of Publication
2017
Journal
Hum Mol Genet
Volume
26
Issue
21
Pages
4257-4266
Date Published
2017 11 01
ISSN
1460-2083
DOI
10.1093/hmg/ddx314
PubMed ID
28973171
PubMed Central ID
PMC5886288
Links
Grant list
MC_U105697135 / Medical Research Council / United Kingdom
MC_UP_1002/1 / Medical Research Council / United Kingdom
R01 GM077465 / GM / NIGMS NIH HHS / United States
R35 GM122455 / GM / NIGMS NIH HHS / United States