Abstract
BackgroundThe Rett Syndrome (RTT) brain displays regional histopathology and volumetric reduction, with frontal cortex showing such abnormalities, whereas the occipital cortex is relatively less affected.ResultsUsing microarrays and quantitative PCR, the mRNA expression profiles of these two neuroanatomical regions were compared in postmortem brain tissue from RTT patients and normal controls. A subset of genes was differentially expressed in the frontal cortex of RTT brains, some of which are known to be associated with neurological disorders (clusterin and cytochrome c oxidase subunit 1) or are involved in synaptic vesicle cycling (dynamin 1). RNAi-mediated knockdown of MeCP2 in vitro, followed by further expression analysis demonstrated that the same direction of abnormal expression was recapitulated with MeCP2 knockdown, which for cytochrome c oxidase subunit 1 was associated with a functional respiratory chain defect. Chromatin immunoprecipitation (ChIP) analysis showed that MeCP2 associated with the promoter regions of some of these genes suggesting that loss of MeCP2 function may be responsible for their overexpression.ConclusionsThis study has shed more light on the subset of aberrantly expressed genes that result from MECP2 mutations. The mitochondrion has long been implicated in the pathogenesis of RTT, however it has not been at the forefront of RTT research interest since the discovery of MECP2 mutations. The functional consequence of the underexpression of cytochrome c oxidase subunit 1 indicates that this is an area that should be revisited.
Highlights
The Rett Syndrome (RTT) brain displays regional histopathology and volumetric reduction, with frontal cortex showing such abnormalities, whereas the occipital cortex is relatively less affected
There is a decrease in the size of the RTT brain which is partially explained by a decrease in the size of individual
We acknowledge that expression patterns may change with age, the genes that were analyzed following initial microarray analysis were (1) differentially expressed in an in vitro RNA interference (RNAi)-mediated knockdown system and (2) differentially expressed between the frontal and occipital cortex of the individual RTT brain samples, independent of any comparison with the control brain samples
Summary
The Rett Syndrome (RTT) brain displays regional histopathology and volumetric reduction, with frontal cortex showing such abnormalities, whereas the occipital cortex is relatively less affected. Rett syndrome (RTT) is a neurodevelopmental disorder and a leading cause of severe intellectual disability in females [1]. One of the most prominent neuropathological features of RTT is the impairment of normal neuronal development, primarily at the synapse with a disruption to the normal development of axodendritic connections. The RTT neuropathology manifests in specific regions of the brain. A diagnosis of RTT is typically made on the evolving clinical phenotype, most cases have a genetic basis and are caused by mutations in the X-linked MECP2 gene (Methyl-CpG Binding Protein 2) [6] The shortening and thickening of dendritic branches are observed in the same brain regions that have a decreased volume, for example layers III and V of the frontal, motor and inferior temporal regions, whereas the dendrites of the occipital cortex are comparatively less affected [4].
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