# Fragile X Premutations, Mechanisms and Modifiers

> **NIH NIH P50** · BAYLOR COLLEGE OF MEDICINE · 2024 · $1,800,000

## Abstract

Fragile X Premutations- Mechanisms and Modifiers
Fragile X-associated disorders are a heterogeneous group of conditions arising from alterations
in the size, content, and epigenetic state of a polymorphic CGG repeat within the FMR1 gene.
Described as the first repeat expansion disorder nearly 30 years ago, FMR1 CGG repeat
expansions are both an important cause of neurological, reproductive and neurodevelopmental
disease as well as an archetype for understanding repeat expansions and the mechanisms by
which they elicit dysfunction. Work over past decades delineated the native functions of the
fragile X protein, FMRP, and the consequences of its loss and the explored toxic gain-of
function mechanisms (RNA-mediated toxicity via protein sequestration, and protein mediated
toxicity from Repeat associated non-AUG (RAN) translation) elicited by transcribed CGG
repeats. Despite these efforts, we still lack effective therapies for any of the cardinal Fragile X-
associated disorders.
Here we propose a paradigm shift in our approach to FX associated disorders. Rather than
focusing solely on specific diseases (Fragile X Syndrome (FXS), fragile X-associated
tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency
(FXPOI)), the Center structure enables us to directly engage the mechanistic cross-talk between
conditions and between the FMR1 locus and related repeat expansion disorders. Our central
hypothesis is that a deeper understanding of genetic factors which underlie clinical disease
onset and penetrance in premutation associated disorders and an exploration of native CGG
repeat functions will reveal novel insights into both how repeats cause disease and how they
might be targeted therapeutically. Led by a multidisciplinary team featuring many leaders in the
Fragile X field, we will address this hypothesis in three cohesive projects all focused on
premutation disorders by using data-driven genomic and bioinformatics approaches coupled
with emerging tools and integrative model systems. By pooling our substantial data, expertise
and resources, we will pursue a deeper understanding of FX premutation pathogenic
mechanisms and define a series of robust and viable targets for therapeutic development
across Fragile X-associated disorders.

## Key facts

- **NIH application ID:** 10907680
- **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:** $1,800,000
- **Award type:** 5
- **Project period:** 2020-09-25 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907680

## Citation

> US National Institutes of Health, RePORTER application 10907680, Fragile X Premutations, Mechanisms and Modifiers (5P50HD104463-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10907680. Licensed CC0.

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