# Defining the Role of Aminoacyl-tRNA Synthetases in Human Health and Disease

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $385,624

## Abstract

PROJECT ABSTRACT
Aminoacyl-tRNA synthetases (ARSs) are a ubiquitously expressed, essential class of enzymes responsible for
ligating amino acids to cognate tRNA molecules. Importantly, 34 of the 37 loci encoding an ARS have been
implicated in myriad dominant and recessive clinical phenotypes, making these enzymes a major contributor to
human inherited disease. It is now important to systematically assess the role of ARS alleles in human disease
phenotypes and to determine how they affect protein translation. These data will provide insight into the
molecular pathology of disease-associated ARS alleles, which affect a wide range of tissues. Furthermore,
defining the molecular mechanisms of ARS-associated disease will allow rapid patient diagnosis through
distinguishing pathogenic from non-pathogenic alleles in human populations. We and others have shown that
disease-associated ARS alleles cause a loss-of-function effect on tRNA charging. However, a number of
critical questions remain, including: What is the full spectrum of disease phenotypes caused by ARS alleles?
What is the subset of ARS alleles in human populations that are pathogenic? How do loss-of-function
missense ARS variants cause dominant peripheral neuropathy? and How do loss-of-function ARS variants
affect mRNA processing and protein expression? Here, we employ multiple established and complementary
model systems—computational, biochemical, cellular, yeast, worm, and mouse—to address the above
questions. Our efforts will include: (1) studying patient populations to implicate newly identified ARS variants in
disease onset; (2) deeply interrogating ARS-related phenotypes using worm and mouse models; (3)
systematically determining the effect of ARS variants on gene function using massively parallel mutagenesis
and mammalian cell viability assays; (4) testing neuropathy-associated ARS variants for both dominant-
negative and toxic gain-of-function effects in vitro and in vivo; and (5) testing loss-of-function, disease-
associated ARS variants for an effect on protein translation via ribosomal profiling and mass spectrometry in
yeast, worm, and mouse models. In sum, the areas of study outlined in this proposal will dramatically improve
our understanding of how certain ARS alleles give rise to dominant and recessive human disease phenotypes.

## Key facts

- **NIH application ID:** 9931744
- **Project number:** 1R35GM136441-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Anthony Antonellis
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,624
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931744

## Citation

> US National Institutes of Health, RePORTER application 9931744, Defining the Role of Aminoacyl-tRNA Synthetases in Human Health and Disease (1R35GM136441-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9931744. Licensed CC0.

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