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.

Public Health Relevance

Mutations in aminoacyl-tRNA synthetases cause dominant peripheral neuropathies and recessive multi-system disorders with neurological components. Understanding the clinical and genetic heterogeneity of ARS-related diseases and the mechanisms of how these mutations cause disease will provide the required foundation for therapeutic development for patients with aminoacyl-tRNA synthetase mutations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS113515-01
Application #
9832449
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nuckolls, Glen H
Project Start
2019-12-15
Project End
Budget Start
2019-12-15
Budget End
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Genetics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109