Fragile X is unique among neurogenetic conditions because it is the only such disorder with a dose-responsemechanism based on a single gene (CGG-repeat-dependence of phenotypes). Also, it produces varyingoutcomes as a result of different pathogenic mechanisms related to FMR1 gene dysregulation - low/absentFMR1 protein (FMRP) in fragile X syndrome; elevated levels of 'toxic' FMR1 RNA. As a result of thesecharacteristics, fragile X provides a unique model for developing a 'molecules to mind' explanation of aneurogenetic disorder that can then be used to generate hypotheses about the genetic bases of disorderswith less clear molecular mechanisms. Thus, the overall objective of this component is to understand howvariations in the mutation of a single gene (FMR1) produce a spectrum of cognitive dysfunction in bothchildhood and adulthood. To this end, we will generate the first detailed neurocognitive profile of anintegrated set of cognitive domains that preliminary data suggest are highly vulnerable to changes in theexpression of FMRP. The profile will consist of data derived from hypothesis-driven experimental cognitiveprocessing tasks and magnetic resonance imaging (MRI) methods that will produce structural, functional andconnectivity measures. We will refer to this profile as the FMR1 Sensitive Neurocognitive Profile (FSNP). Itwill focus on spatiotemporal, memory, numerical, and executive cognitive functions. It will be characterized inchildren and adults who have the fragile X full mutation and extended to smaller alleles in the premutationrange, and to unaffected (normal repeat) controls. In our investigations we will consider the effect of twocontinuous variables: FMRP expression level and FMR1 mRNA level, and one categorical variable: phase ofdevelopment (childhood or adulthood). There will be extensive interaction with other components. WithProject 1 we will share the neurocognitive specification of phenotypes that will foster understanding ofmolecular mechanisms and treatment effects and we will be dependent on their molecular and cellularassessments. With Project 2 there will be a bidirectional feed of behavioral and MRI assessments, especiallyto drive investigations of the 'mixed phenotype' where FMRP and FMR1 RNA changes may interact. Data(and methods) shared between Projects 3 and 4 will extend lifespan analyses, clarify neurochemicalmechanisms and neural progressions toward FXTAS, and drive novel MRI analysis method development.
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