Patterns and mechanisms of repeat instability in FXTAS

Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by trinucleotide ‘premutation’ repeat expansions at the FMR1 locus, presents with late-onset tremor, ataxia, neuropsychiatric symptoms, and cognitive decline. One challenge in addressing FXTAS is the significant clinical heterogeneity, but the source of this remains unresolved. In many ways, variability in the repeat expansion itself could also hold the key to unlocking innovative new therapeutic strategies. However, historical challenges in parsing repetitive genomic regions in heterogeneous brain tissue have stymied understanding of the underlying physiology. Furthermore, fundamental differences in the biology in animal model systems limit their utility in unraveling endogenous mechanisms of trinucleotide pathogenicity. Thus, there are no therapeutic interventions currently available to treat FXTAS, or any of the Fragile X-related conditions for that matter. Given the relatively high prevalence of the FMR1 premutation in the general population, there is a critical unmet need to better understand FMR1 repeat variability. Specifically, we will apply cutting edge sequencing and analytic approaches, that will allow us to interrogate the neurogenetic mechanisms of FMR1 regulation directly in the human condition. This work is innovative in integrating cutting edge approaches to answer long-standing questions about FXTAS, with broader relevance not just for FXTAS and Fragile X-related conditions but neurologic repeat expansion disorders as well. We expect this project will elucidate the genetic and cellular mechanisms mediating FMR1 repeat instability, which in turn will accelerate therapeutic development and improve clinical care. Project Number: 1R01NS134544-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Caroline Dias | Institution: UNIVERSITY OF COLORADO DENVER, Aurora, CO | Award Amount: $619,977 | Activity Code: R01 | Study Section: Pathophysiological Basis of Mental Disorders and Addictions Study Section[PMDA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11293333