# Defining the Role of Cysteinyl-tRNA Synthetase Variants in Neurological Disease > **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $38,201 ## Abstract ABSTRACT My long-term goal as a physician-scientist is to study the molecular mechanisms of neurogenetic disorders, with the ultimate aim of developing therapies. Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that charge tRNA with cognate amino acids. To date, mutations in 33 of the 37 ARS-encoding loci have been implicated in dominant peripheral neuropathies or recessive multi-system disorders; however, the allelic and locus heterogeneity of ARS-related phenotypes is incomplete, and the molecular, cellular, and organismal consequences of ARS mutations are poorly understood. Cysteinyl-tRNA synthetase (CARS) encodes the enzyme that charges tRNACYS with cysteine in the cytoplasm. To date, CARS variants have not been implicated in any human disease phenotype. In collaboration with the NIH Undiagnosed Diseases Program, we identified four patients from three families with a complex syndrome that includes microcephaly, developmental delay, and axonal peripheral neuropathy; each patient carries bi-allelic CARS variants. Clinical and genetic evidence are supportive of CARS mutation pathogenicity, and protein expression studies and yeast complementation assays indicate that each CARS variant causes a loss-of-function effect. While a loss-of- function molecular pathology is common to recessive disease-associated ARS variants, the downstream effects on cellular, tissue, and organism function are poorly defined. Additionally, the role of CARS variants in dominant disease has not been explored. To investigate the role of CARS variants in recessive and dominant neurological disease, we will: (1) study the effect of patient mutations implicated in recessive disease on protein translation in the brain; and (2) generate loss-of-function mutations in CARS and investigate the potential for dominant neurotoxicity. This work will provide insight into the pathogenic mechanism of CARS variants, reveal potential therapeutic targets, and expand the clinical and locus heterogeneity of ARS- associated disease. Importantly, this project will allow me to develop the skills necessary for a research career focused on understanding the mechanisms of human inherited disease. ## Key facts - **NIH application ID:** 10086000 - **Project number:** 5F31NS113515-02 - **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR - **Principal Investigator:** Molly Kuo - **Activity code:** F31 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $38,201 - **Award type:** 5 - **Project period:** 2019-07-01 → 2021-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10086000 ## Citation > US National Institutes of Health, RePORTER application 10086000, Defining the Role of Cysteinyl-tRNA Synthetase Variants in Neurological Disease (5F31NS113515-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10086000. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*