# FXTAS: Mechanisms and Modifiers

> **NIH NIH P50** · BAYLOR COLLEGE OF MEDICINE · 2024 · $1,229,118

## Abstract

SUMMARY
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects
individuals with premutation alleles (55–~200 CGG repeats) in fragile X mental retardation 1 (FMR1). Common
features of FXTAS include progressive intention tremor, gait ataxia, Parkinsonism, and cognitive decline.
Penetrance is age-dependent and reaches ~75% in male carriers by age 80. Up to ~15% of women with
premutations also show symptoms of FXTAS. The neuropathological hallmarks of FXTAS include ubiquitin-
positive intranuclear inclusions throughout the brain and marked dropout of Purkinje neurons in the cerebellum.
At the molecular level, FMR1 premutation alleles exhibit a 2 to 8-fold increase in FMR1 mRNA and expression
of mutant mRNAs containing long (~100) CGG triplets has been shown to be toxic in cell and animal models.
Current data support two non-mutually exclusive molecular pathogenesis mechanisms for FXTAS: 1) RNA gain-
of-function, in which the expression of expanded CGGs in RNA (rCGG) interferes with a subset of RNA-binding
proteins (RBPs), functionally limiting their availability through sequestration, and 2) Repeat-associated non-AUG
(RAN) translation, whereby translation through the rCGG (and/or antisense rCCG) repeats leads to the
production of toxic homo-polypeptides, the most abundant of which is FMRpolyGlycine (FMRpolyG), that in turn
interfere with cellular functions. Multiple mouse models have been developed and used by us and others to study
these mechanisms. Previous work by the Nelson, Todd, Allen and Jin groups using model organisms (flies, mice)
and cell models has identified several RBPs affected by expression of rCGGs. Among these are Pur α, hnRNP
A2/B1, DROSHA/DGCR8, and TDP43. Increasing expression of these proteins can modulate rCGG-mediated
toxicity in model systems, supporting the RNA-mediated sequestration model of FXTAS. In addition, RAN
translation products are found in patient inclusions and mouse models and appear to also confer toxicity in
numerous studies. In studies to determine the contributions of both the RAN translation and RBP sequestration
mechanisms to FXTAS pathogenesis, we have generated transgenic lines of mice that express hnRNP A2/B1
and suppression of rCGG repeat-mediated toxicity without alteration of FMRpolyG positive inclusions. Parallel
efforts at the Emory Fragile X Center used whole genome sequence (WGS) analysis of premutation carriers with
early or late onset of FXTAS, combined with fly genetic screens to identify additional genetic modifiers that
influence age of onset of FXTAS. Understanding the role of variation in these genes could suggest candidate
therapeutic targets. In this application, we propose to confirm and extend identification of genetic modifiers
through sequence analysis and analyze potential modifiers of FXTAS identified at Emory using human genetics
and model system studies at Baylor, Emory and Michigan using additional fly, cell and mouse models....

## Key facts

- **NIH application ID:** 10907684
- **Project number:** 5P50HD104463-05
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** David Loren Nelson
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,229,118
- **Award type:** 5
- **Project period:** 2020-09-25 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907684

## Citation

> US National Institutes of Health, RePORTER application 10907684, FXTAS: Mechanisms and Modifiers (5P50HD104463-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10907684. Licensed CC0.

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