Program in Systems Biology; Program in Molecular Medicine
Biochemical Phenomena, Metabolism, and Nutrition | Cellular and Molecular Physiology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Enzymes and Coenzymes | Genetic Phenomena | Genetics and Genomics | Nutritional and Metabolic Diseases | Systems and Integrative Physiology
Mutations in human metabolic genes can lead to rare diseases known as inborn errors of human metabolism. For instance, patients with loss-of-function mutations in either subunit of propionyl-CoA carboxylase suffer from propionic acidemia because they cannot catabolize propionate, leading to its harmful accumulation. Both the penetrance and expressivity of metabolic disorders can be modulated by genetic background. However, modifiers of these diseases are difficult to identify because of the lack of statistical power for rare diseases in human genetics. Here, we use a model of propionic acidemia in the nematode Caenorhabditis elegans to identify genetic modifiers of propionate sensitivity. Using genome-wide association (GWA) mapping across wild strains, we identify several genomic regions correlated with reduced propionate sensitivity. We find that natural variation in the putative glucuronosyltransferase GLCT-3, a homolog of human B3GAT, partly explains differences in propionate sensitivity in one of these genomic intervals. We demonstrate that loss-of-function alleles in glct-3 render the animals less sensitive to propionate. Additionally, we find that C. elegans has an expansion of the glct gene family, suggesting that the number of members of this family could influence sensitivity to excess propionate. Our findings demonstrate that natural variation in genes that are not directly associated with propionate breakdown can modulate propionate sensitivity. Our study provides a framework for using C. elegans to characterize the contributions of genetic background in models of human inborn errors in metabolism.
Propionates, Caenorhabditis elegans, Genome-wide association studies, Quantitative trait loci, Genomics, Chromosome mapping, Inborn errors of metabolism, Heredity
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Copyright: © 2020 Na et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
Na H, Zdraljevic S, Tanny RE, Walhout AJM, Andersen EC. Natural variation in a glucuronosyltransferase modulates propionate sensitivity in a C. elegans propionic acidemia model. PLoS Genet. 2020 Aug 28;16(8):e1008984. doi: 10.1371/journal.pgen.1008984. PMID: 32857789; PMCID: PMC7482840. Link to article on publisher's site
Na H, Zdraljevic S, Tanny RE, Walhout AJ, Andersen EC. (2020). Natural variation in a glucuronosyltransferase modulates propionate sensitivity in a C. elegans propionic acidemia model. Open Access Articles. https://doi.org/10.1371/journal.pgen.1008984. Retrieved from https://escholarship.umassmed.edu/oapubs/4338
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Biochemical Phenomena, Metabolism, and Nutrition Commons, Cellular and Molecular Physiology Commons, Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Enzymes and Coenzymes Commons, Genetic Phenomena Commons, Genetics and Genomics Commons, Nutritional and Metabolic Diseases Commons, Systems and Integrative Physiology Commons