|
|
|
Rett syndrome is a severe neurological disorder that predominantly affects young girls and is believed to be one of the most common genetic causes of severe mental retardation in females. Girls develop learning, behavioural and mobility impairments and require constant care for the rest of their lives. Even feeding presents a problem as girls lose hand dexterity and develop stereotypical hand wringing motions.
Mutations in the Methyl-CpG-Binding Protein 2 (Mecp2) gene are found in most cases of this condition. We have developed models of this disorder by introducing changes to the Mecp2 gene in mice. These mice emulate many social and behavioural aspects seen in Rett syndrome patients.
Impact of X-chromosome activity
There are wide variations in disease severity presented by patients and we have investigated two possible causes for this. Mecp2 is found on the X chromosome. As girls have two X chromosomes, one is randomly inactivated in each cell. We have looked at whether a mutated copy of the Mecp2 gene on the X chromosome results in that chromosome’s preferential inactivation, therefore skewing the number of affected cells in the patient’s brain. We have also investigated whether the parental origin of the affected X chromosome has an impact on the ability of the cells to proliferate.
Effect of environmental enrichment
In an investigation of the behavioural attributes of our mice with Mecp2 mutations, we have found that these mice display reduced motor skills and diminished capacity to learn and retain memory. By analysing the pattern of gene expression in the brains of these mice, we have identified genes which are progressively dysregulated as the syndrome becomes more pronounced. Currently we are trying to decipher the regions of the brain where Mecp2 activity is most critically required by looking at the brain regions that the mutant cells contribute to and the corresponding impairment of behavioural activity. This knowledge will provide the foundations for devising possible therapies in which treatment may be targeted to the affected brain parts.
Mecp2 and Cdkl5 genes in Rett Syndrome: Downstream molecular activity
Our recent work indicates that mutations in another gene, CDKL5, result in Rett girls who have a high level of seizures from a young age. We have previously characterised our Mecp2-deficient mice using molecular and behavioural approaches and identified, in specific regions of the brain, a number of putative genes and proteins whose expression was dysregulated and could potentially contribute to the Rett phenotype. We wish to reinforce and build on these findings by analysing the morphological, behavioural and molecular deficiencies within these mice. This will include testing the activity status of the MECP2 protein and the activity of downstream genes/proteins in the brains of mice lacking functional Cdkl5, which we are currently generating, given the overlap in symptoms seen in patients with mutations of these genes. Comparing the combined molecular pathways affected in Cdkl5 deficient mice, which parallel those identified in Mecp2 mutants, will highlight conserved mechanisms of phenotype development. A greater understanding of these processes will lead to the development of more effective strategies to minimise or circumvent the symptoms associated with Rett syndrome and related clinical phenotypes.
This project is a collaboration with the team led by Professor Christodoulou of the Western Sydney Genetics Program.
|
|