Cargando…
Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome
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 OXPH...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886288/ https://www.ncbi.nlm.nih.gov/pubmed/28973171 http://dx.doi.org/10.1093/hmg/ddx314 |
_version_ | 1783312110633091072 |
---|---|
author | Garone, Caterina D’Souza, Aaron R Dallabona, Cristina Lodi, Tiziana Rebelo-Guiomar, Pedro Rorbach, Joanna Donati, Maria Alice Procopio, Elena Montomoli, Martino Guerrini, Renzo Zeviani, Massimo Calvo, Sarah E Mootha, Vamsi K DiMauro, Salvatore Ferrero, Ileana Minczuk, Michal |
author_facet | Garone, Caterina D’Souza, Aaron R Dallabona, Cristina Lodi, Tiziana Rebelo-Guiomar, Pedro Rorbach, Joanna Donati, Maria Alice Procopio, Elena Montomoli, Martino Guerrini, Renzo Zeviani, Massimo Calvo, Sarah E Mootha, Vamsi K DiMauro, Salvatore Ferrero, Ileana Minczuk, Michal |
author_sort | Garone, Caterina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5886288 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-58862882018-04-09 Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome Garone, Caterina D’Souza, Aaron R Dallabona, Cristina Lodi, Tiziana Rebelo-Guiomar, Pedro Rorbach, Joanna Donati, Maria Alice Procopio, Elena Montomoli, Martino Guerrini, Renzo Zeviani, Massimo Calvo, Sarah E Mootha, Vamsi K DiMauro, Salvatore Ferrero, Ileana Minczuk, Michal Hum Mol Genet Articles 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. Oxford University Press 2017-11-01 2017-08-25 /pmc/articles/PMC5886288/ /pubmed/28973171 http://dx.doi.org/10.1093/hmg/ddx314 Text en © The Author 2017. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Garone, Caterina D’Souza, Aaron R Dallabona, Cristina Lodi, Tiziana Rebelo-Guiomar, Pedro Rorbach, Joanna Donati, Maria Alice Procopio, Elena Montomoli, Martino Guerrini, Renzo Zeviani, Massimo Calvo, Sarah E Mootha, Vamsi K DiMauro, Salvatore Ferrero, Ileana Minczuk, Michal Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome |
title | Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome |
title_full | Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome |
title_fullStr | Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome |
title_full_unstemmed | Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome |
title_short | Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome |
title_sort | defective mitochondrial rrna methyltransferase mrm2 causes melas-like clinical syndrome |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886288/ https://www.ncbi.nlm.nih.gov/pubmed/28973171 http://dx.doi.org/10.1093/hmg/ddx314 |
work_keys_str_mv | AT garonecaterina defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT dsouzaaaronr defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT dallabonacristina defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT loditiziana defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT rebeloguiomarpedro defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT rorbachjoanna defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT donatimariaalice defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT procopioelena defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT montomolimartino defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT guerrinirenzo defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT zevianimassimo defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT calvosarahe defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT moothavamsik defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT dimaurosalvatore defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT ferreroileana defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome AT minczukmichal defectivemitochondrialrrnamethyltransferasemrm2causesmelaslikeclinicalsyndrome |