Fragile X Related Genes in Mental Retardation and Development
I. Development of models and assays for testing FMR1 and paralog functions in mice.
This aim will continue development and studies of mice lacking each of the three genes singly and in combination. It will characterize the circadian defect found in mice lacking Fmr1 and Fxr2 , and define functions of Fxr1 through analysis of knockout and hypomophic mutants for this gene. Combinations of gene ablations in specific tissues will provide the ability to test hypotheses regarding specific gene dysfunctions in the absence of these RNA binding proteins.
II. Development and use of mouse models to determine the mechanistic basis of Fragile X-premutation-associated tremor ataxia syndrome.
Two mouse models are currently under analysis. Differences and similarities between these models will provide insight into the mechanism by which CGG premutation can lead to neuronal loss in the vertebrate brain. Additional models are proposed to accelerate onset of the phenotype by overexpression in specific neurons and to evaluate the role of mRNA carrying elongated CGG in the disease. Several approaches will be employed to define the constituents of the ubiquitin-positive nuclear inclusions in order to determine their role in the disease, and modifiers will be tested genetically and biochemically.
This project includes investigators at Erasmus University (Ben Oostra) in Rotterdam, The Netherlands funded as a subcontract.
Relevance of the project to IDDRC mission:
Fragile X syndrome is the leading cause of inherited mental retardation.