# Defining post-transcriptional gene regulation in FMRP-deficiency usingmiRNA:target chimeras

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $487,264

## Abstract

Fragile X Syndrome (FXS) is the most common monogenic cause of Autism
spectrum disorder (ASD), a group of complex neurodevelopmental disorders
characterized by core diagnostic impairments in social interactions and
communication, restricted repetitive behaviors and interests, and an association
with intellectual disability. FXS results from deficiency in expression of the FMR1
gene encoding Fragile X Mental Retardation Protein (FMRP). An early overgrowth
of neurons and excessive immature synaptic contacts have been observed in
brains of children with FXS, as well as in the Fmr1 KO mouse model. At a
molecular level, aberrant excessive protein synthesis, with altered production of
key synaptic proteins, is implicated in the atypical neural and synaptic overgrowth.
While FMRP loss can lead to excessive protein synthesis, mechanisms altering
the gene-target selectivity of protein synthesis to produce the distinct phenotypes
of FMRP-deficiency are incompletely understood. MicroRNAs (miRNAS) are small
RNAs which can selectively target gene transcripts for repression in the RNA-
induced silencing complex (RISC). FXS has been linked to misregulation of
miRNAs and miRNA-mediated gene repression for over 15 years, but broad
knowledge of alterations in targeted transcripts has been lacking. We propose to
carry out genome-wide quantitative comparisons of RISC-mediated gene targeting
in the wildtype and FMRP-deficient setting using both mice and human neurons.
Directed by preliminary data, we will investigate the candidate let-7 miRNA family
to test the hypothesis that dysregulation of let-7 miRNA biogenesis in the Fmr1 KO
mouse contributes to altered repression of pro-growth mRNAs and downstream
behavioral and neuroanatomical phenotypes. A multipronged approach for
mechanistic investigation and prioritizing gene targets and pathways from
genome-wide assessments will be followed by intervention to assess the functional
consequences for FXS-associated phenotypes with the goal of enhancing our
understanding of FMRP function and providing new molecular targets for
intervention in phenotypes resulting from deficiency of FMRP.

## Key facts

- **NIH application ID:** 10755355
- **Project number:** 5R01MH129292-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** MOLLIE Katherine MEFFERT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $487,264
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755355

## Citation

> US National Institutes of Health, RePORTER application 10755355, Defining post-transcriptional gene regulation in FMRP-deficiency usingmiRNA:target chimeras (5R01MH129292-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10755355. Licensed CC0.

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