# Defining the Molecular Pathology of Neuropathy-associated Aminoacyl-tRNA Synthetase Mutations

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $37,394

## Abstract

ABSTRACT
A major goal of my career is to become an independent scientist studying the mechanisms of rare genetic
disorders, with the ultimate goal of developing therapies. Charcot-Marie-Tooth (CMT) disease is a debilitating
inherited peripheral neuropathy that affects 1 in 2,500 individuals worldwide. However, a rare, autosomal
dominant form of CMT is caused by mutations in five genes encoding an aminoacyl-tRNA synthetase (ARS).
Aminoacyl-tRNA synthetases ligate tRNA molecules to cognate amino acids for use in protein translation.
Although the majority of CMT-associated mutations impair this catalytic activity, the precise molecular
pathology is not understood. Interestingly, neuropathy-associated ARS mutations are all missense changes;
frameshift and nonsense mutations in ARS genes are not associated with CMT disease and are present in
unaffected individuals, ruling out haploinsufficiency. Additionally, the five ARS genes implicated in CMT encode
homodimeric enzymes. These observations raise the possibility of a dominant-negative effect that causes a
severe depletion of ARS activity, which may breach a minimum threshold of enzyme function required for
healthy peripheral nerves. Under a dominant-negative mechanism: (i) neuropathy-associated ARS missense
variants should directly impact protein translation and the wild-type enzyme should rescue the neuropathic
phenotype; and (ii) loss-of-function missense variants in any dimeric ARS enzyme should be potentially
deleterious to peripheral nerves. To determine if ARS-associated neuropathy arises due to reduced ARS
activity, we will: (1) study an established CMT-causing ARS mutation to define the molecular pathology; and
(2) engineer loss-of-function mutations in a dimeric ARS enzyme not-yet-associated with CMT disease and test
for neurotoxicity in vivo. These experiments will strengthen our understanding of the mechanism of ARS-
mediated CMT disease, and will directly test if improving ARS function is a relevant therapeutic goal for patient
populations. Importantly, this project will allow me to develop the skill set necessary for a research career
focused on defining the molecular mechanisms of rare, inherited human diseases.

## Key facts

- **NIH application ID:** 9852889
- **Project number:** 5F31NS108510-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Rebecca Meyer Schuman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,394
- **Award type:** 5
- **Project period:** 2019-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852889

## Citation

> US National Institutes of Health, RePORTER application 9852889, Defining the Molecular Pathology of Neuropathy-associated Aminoacyl-tRNA Synthetase Mutations (5F31NS108510-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852889. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*