{"id":{"repo_id":"uwo","oai_identifier":"oai:uwo.scholaris.ca:20.500.14721/39363"},"canonical_url":"https://search.dev.ndltd.org/etd/uwo/oai:uwo.scholaris.ca:20.500.14721/39363","repository":{"repo_id":"uwo","name":"Western University","base_url":"https://uwo.scholaris.ca/server/oai/request"},"display":{"title":"Characterizing CMT-causing variants in tryptophanyl- tRNA synthetase","abstract":"Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that link amino acids to their cognate tRNAs. Neurological conditions, such as Charcot-Marie-Tooth (CMT) disease, have been linked to variants identified in these enzymes. I created a humanized yeast model to assess the underlying disease-causing mechanism associated with two CMT variants, H257R and D314G, present in the human tryptophanyl-tRNA synthetase (WARS1). Using proteomic analysis, protein biochemistry, and yeast growth assays, I found that while both variants retain their typical structure, their stability and function differ. D314G exhibited decreased stability and triggers stress- related pathways, whereas H257R showed mild functional impairment that can be ameliorated by tryptophan supplementation. This work presents the first WARS1 humanized yeast model that was subsequently used to better understand the disease- causing molecular mechanism of WARS1 variants and investigate potential therapeutic approaches, such as amino acid supplementation.","abstract_html":"Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that link amino acids to their cognate tRNAs. Neurological conditions, such as Charcot-Marie-Tooth (CMT) disease, have been linked to variants identified in these enzymes. I created a humanized yeast model to assess the underlying disease-causing mechanism associated with two CMT variants, H257R and D314G, present in the human tryptophanyl-tRNA synthetase (WARS1). Using proteomic analysis, protein biochemistry, and yeast growth assays, I found that while both variants retain their typical structure, their stability and function differ. D314G exhibited decreased stability and triggers stress- related pathways, whereas H257R showed mild functional impairment that can be ameliorated by tryptophan supplementation. This work presents the first WARS1 humanized yeast model that was subsequently used to better understand the disease- causing molecular mechanism of WARS1 variants and investigate potential therapeutic approaches, such as amino acid supplementation.","abstract_has_math":false,"creators":["Wu, Fanqi"],"institution":"The University of Western Ontario","degree_name":"M Sc","degree_level":null,"degree_discipline":"Biochemistry","degree_department":null,"school":null,"contributors":[],"advisors":["Heinemann, Ilka"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-12-10","date_published":"2025-12-10","updated_at":"2026-07-27T21:56:13Z","subjects":["WARS1","aminoacyl-tRNA synthetase","neuropathy","Charcot-Marie-Tooth disease","yeast model","proteomics","protein stability."],"languages":["en"],"rights":["Attribution-NonCommercial-NoDerivatives 4.0 International"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/20.500.14721/39363","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Heinemann, Ilka"]},{"key":"dc:creator","label":"Author","values":["Wu, Fanqi"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-02-02T19:08:53Z"]},{"key":"dc:date.issued","label":"Date","values":["2025-12-10"]},{"key":"dc:publisher","label":"Institution","values":["The University of Western Ontario"]},{"key":"dc:type","label":"Dc Type","values":["thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biochemistry"]},{"key":"thesis:degree_name","label":"Degree Name","values":["M Sc"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["The University of Western Ontario"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["WARS1","aminoacyl-tRNA synthetase","neuropathy","Charcot-Marie-Tooth disease","yeast model","proteomics","protein stability."]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Attribution-NonCommercial-NoDerivatives 4.0 International"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/20.500.14721/39363"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that link amino acids to their cognate tRNAs. Neurological conditions, such as Charcot-Marie-Tooth (CMT) disease, have been linked to variants identified in these enzymes. I created a humanized yeast model to assess the underlying disease-causing mechanism associated with two CMT variants, H257R and D314G, present in the human tryptophanyl-tRNA synthetase (WARS1). Using proteomic analysis, protein biochemistry, and yeast growth assays, I found that while both variants retain their typical structure, their stability and function differ. D314G exhibited decreased stability and triggers stress- related pathways, whereas H257R showed mild functional impairment that can be ameliorated by tryptophan supplementation. This work presents the first WARS1 humanized yeast model that was subsequently used to better understand the disease- causing molecular mechanism of WARS1 variants and investigate potential therapeutic approaches, such as amino acid supplementation."]},{"key":"dc:title","label":"Title","values":["Characterizing CMT-causing variants in tryptophanyl- tRNA synthetase"]}]}],"canonical_facts":{"dc:contributor.advisor":["Heinemann, Ilka"],"dc:creator":["Wu, Fanqi"],"dc:date.accessioned":["2026-02-02T19:08:53Z"],"dc:date.issued":["2025-12-10"],"dc:description.abstract":["Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that link amino acids to their cognate tRNAs. Neurological conditions, such as Charcot-Marie-Tooth (CMT) disease, have been linked to variants identified in these enzymes. I created a humanized yeast model to assess the underlying disease-causing mechanism associated with two CMT variants, H257R and D314G, present in the human tryptophanyl-tRNA synthetase (WARS1). Using proteomic analysis, protein biochemistry, and yeast growth assays, I found that while both variants retain their typical structure, their stability and function differ. D314G exhibited decreased stability and triggers stress- related pathways, whereas H257R showed mild functional impairment that can be ameliorated by tryptophan supplementation. This work presents the first WARS1 humanized yeast model that was subsequently used to better understand the disease- causing molecular mechanism of WARS1 variants and investigate potential therapeutic approaches, such as amino acid supplementation."],"dc:identifier.uri":["https://hdl.handle.net/20.500.14721/39363"],"dc:language.iso":["en"],"dc:publisher":["The University of Western Ontario"],"dc:rights":["Attribution-NonCommercial-NoDerivatives 4.0 International"],"dc:subject":["WARS1","aminoacyl-tRNA synthetase","neuropathy","Charcot-Marie-Tooth disease","yeast model","proteomics","protein stability."],"dc:title":["Characterizing CMT-causing variants in tryptophanyl- tRNA synthetase"],"dc:type":["thesis"],"thesis:degree_discipline":["Biochemistry"],"thesis:degree_name":["M Sc"],"thesis:institution_name":["The University of Western Ontario"]},"updated_at":"2026-07-27T21:56:13Z"}