title: Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome.
abstract: Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the X-linked MECP2 gene, which encodes a methyl-CpG binding transcriptional repressor. Using the Mecp2-null mouse (an animal model for RTT) and differential display, we found that mice with neurological symptoms overexpress the nuclear gene for ubiquinol-cytochrome c reductase core protein 1 (Uqcrc1). Chromatin immunoprecipitation demonstrated that MeCP2 interacts with the Uqcrc1 promoter. Uqcrc1 encodes a subunit of mitochondrial respiratory complex III, and isolated mitochondria from the Mecp2-null brain showed elevated respiration rates associated with respiratory complex III and an overall reduction in coupling. A causal link between Uqcrc1 gene overexpression and enhanced complex III activity was established in neuroblastoma cells. Our findings raise the possibility that mitochondrial dysfunction contributes to pathology of the Mecp2-null mouse and may contribute to the long-known resemblance between Rett syndrome and certain mitochondrial disorders.
authors.affiliation: The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, The King's Buildings, Edinburgh EH9 3JR, United Kingdom.
authors.forename: Skirmantas
authors.initials: S
authors.lastname: Kriaucionis
authors.forename: Andrew
authors.initials: A
authors.lastname: Paterson
authors.forename: John
authors.initials: J
authors.lastname: Curtis
authors.forename: Jacky
authors.initials: J
authors.lastname: Guy
authors.forename: Nikki
authors.initials: N
authors.lastname: Macleod
authors.forename: Adrian
authors.initials: A
authors.lastname: Bird
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D014450:Electron Transport Complex III / Q000235:genetics*; D005786:Gene Expression Regulation; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure*; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D015518:Rett Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D014450:Electron Transport Complex III