Rett syndrome: Genetic clues based on mitochondrial changes in muscle

Eeg‐Olofsson, Orvar; Al-Zuhair, A. G. H.; Teebi, Ahmad S.; Al-Essa, Mazen; Opitz, John M.; Reynolds, James F.

doi:10.1002/ajmg.1320320131

Cited by 32 publications

(7 citation statements)

References 10 publications

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“…It was recently noted, however, that a patient with symptoms normally associated with mitochondrial disorders (hypotonia, small stature, developmental delay, and a slight decrease in respiratory chain enzyme activity) harbored mutations in the MECP2 gene (11). This overlap between symptoms of RTT and mitochondrial disorders recalls early reports of structural abnormalities (4,8,9,34) and defects in the electron transport chain (7,8) in mitochondria from skin and muscle biopsies of RTT patients. Moreover, about half of RTT patients were reported to have elevated levels of circulatory lactic or pyruvic acid, which might be caused by defects in the efficiency of the respiratory chain and urea cycle complexes, both of which are mitochondrial (21,25).…”

Section: Discussionmentioning

confidence: 88%

Gene Expression Analysis Exposes Mitochondrial Abnormalities in a Mouse Model of Rett Syndrome

Kriaucionis

Paterson

Curtis

et al. 2006

Molecular and Cellular Biology

193

144

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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.

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Section: Discussionmentioning

confidence: 88%

Gene Expression Analysis Exposes Mitochondrial Abnormalities in a Mouse Model of Rett Syndrome

Kriaucionis

Paterson

Curtis

et al. 2006

Molecular and Cellular Biology

193

144

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“…Rett patients have been reported to harbor mitochondrial structural aberrations and reductions in skeletal muscle OXPHOS complexes I, III, IV, though not II. Furthermore, mice in which MeCP2 is inactivated have increased complex III and core protein 1 gene ( Ugcrc1 ) expression, together with reduced OXPHOS coupling (Eeg-Olofsson et al, 1989; Heilstedt et al, 2002; Kriaucionis et al, 2006). The MeCP2 protein binds to methyl CpG nDNA domains and modulates gene expression, either activation or repression, in part by recruiting histone-modifying enzymes such as deacetylases and methyltransferases (Chen et al, 2003b; Klein et al, 2007).…”

Section: Mitochondrial Explanations For Epigenetic Diseasesmentioning

confidence: 99%

Energetics, epigenetics, mitochondrial genetics

2010

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The epigenome has been hypothesized to provide the interface between the environment and the nuclear DNA (nDNA) genes. Key factors in the environment are the availability of calories and demands on the organism’s energetic capacity. Energy is funneled through glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), the cellular bioenergetic systems. Since there are thousands of bioenergetic genes dispersed across the chromosomes and mitochondrial DNA (mtDNA), both cis and trans regulation of the nDNA genes is required. The bioenergetic systems convert environmental calories into ATP, acetyl-Coenzyme A (acetyl-CoA), S-adenosyl-methionine (SAM), and reduced NAD+. When calories are abundant, ATP and acetyl-CoA phosphorylate and acetylate chromatin, opening the nDNA for transcription and replication. When calories are limiting, chromatin phosphorylation and acetylation are lost and gene expression is suppressed. DNA methylaton via SAM can also be modulated by mitochondrial function. Phosphorylation and acetylation are also pivotal to regulating cellular signal transduction pathways. Therefore, bioenergetics provides the interface between the environment and the epigenome. Consistent with this conclusion, the clinical phenotypes of bioenergetic diseases are strikingly similar to those observed in epigenetic diseases (Angelman, Rett, Fragile X Syndromes, the laminopathies, cancer, etc.), and an increasing number of epigenetic diseases are being associated with mitochondrial dysfunction. This bioenergetic-epigenomic hypothesis has broad implications for the etiology, pathophysiology, and treatment of a wide range of common diseases.

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“…Other hypotheses have also been published viz. X-linked dominant mutation (Hagberg et al 1983;Comings 1986;Zoghbi et al 1990), two mutations at the same locus on the two Xchromosomes (Wahlstr6m 1985;Wahlstr6m and Anvret 1986), mitochondrial mutations (Eeg-Olofsson et al 1989) and gene disruption (Journel et al 1990). These differing hypotheses (including our own) indicate that the genetic basis of the syndrome is still a matter of debate.…”

Section: Hypothesis Ofmentioning

confidence: 98%