# Investigating the Role of Seryl-tRNA Synthetase in Mitochondrial Biology and Human Recessive Disease

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $32,755

## Abstract

ABSTRACT
My long-term professional goal is to study rare human inherited diseases with an emphasis on: (1) defining
disease mechanisms and developing therapeutics; and (2) increasing research and awareness through
participating in science policy. Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that charge tRNA
with cognate amino acids in the cytoplasm and mitochondria; 17 of the 37 nuclear-encoded ARSs act
exclusively in the mitochondria. All 17 mitochondrial ARSs have been implicated in human recessive
diseases with a broad range of clinical phenotypes, often affecting tissues with high energy demands.
Interestingly, certain mitochondrial ARSs cause variable tissue-specific effects, which can depend on the
specific genetic variants that a patient carries. One important example of this observation is mitochondrial
seryl-tRNA synthetase (SARS2), which has been implicated in disease phenotypes ranging from progressive
spastic paresis to HUPRA syndrome (Hyper Uricemia, Pulmonary hypertension, Renal failure in infancy, and
Alkalosis). Currently, there are no genetic or molecular explanations for this clinical heterogeneity.
Furthermore, the number of known pathogenic variants is limited, resulting in a large gap in our knowledge of
the allelic heterogeneity in SARS2-related disease. I will pursue two specific aims to address these issues.
Under Aim 1, I will perform massively parallel cell growth assays on all possible variants in the SARS2 open
reading frame to assess the functional consequences of each variant. These studies will be performed in
haploid (Hap1) cells that harbor: (a) a randomly integrated, 1xFLAG-tagged, doxycycline-inducible wild-type
copy of SARS2; and (b) an endogenous SARS2 null allele. I will transduce these cells with lentiviral libraries
containing all possible SARS2 variants and will quantitate the frequencies of each allele (via next-generation
sequencing) in the presence of doxycycline (i.e., in the presence of wild-type SARS2-1xFLAG) and in the
absence of doxycycline (i.e., in the absence of SARS2-1xFLAG). Variants that are reduced in frequency after
doxycycline removal will be classified as loss-of-function alleles. Under Aim 2, I will generate clonal Hap1
cell lines that carry individual, known pathogenic SARS2 variants that are associated with distinct clinical
phenotypes (i.e., progressive spastic paresis versus HUPRA syndrome). These cell lines will contain an
integrated, inducible SARS2-1xFLAG that can be used to maintain cell viability. I will employ these cell lines
to assess the effect of each variant on protein translation, mitochondrial function, and interactions with
potential SARS2 binding partners. Overall, these studies will: (a) reveal essential regions of the SARS2
protein toward a better understanding of enzyme biology; (b) provide a complete panel of loss-of-function
SARS2 variants toward rapid patient diagnosis; and (c) provide insight into the molecular mechanisms of
SARS2-related disease towa...

## Key facts

- **NIH application ID:** 11009490
- **Project number:** 5F31HD111131-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Christina Del Greco
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $32,755
- **Award type:** 5
- **Project period:** 2023-09-06 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11009490

## Citation

> US National Institutes of Health, RePORTER application 11009490, Investigating the Role of Seryl-tRNA Synthetase in Mitochondrial Biology and Human Recessive Disease (5F31HD111131-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11009490. Licensed CC0.

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