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.

人类新陈代谢基因的突变会导致罕见疾病，即人类新​​陈代谢的先天性错误。例如，丙酰辅酶A羧化酶任一亚基功能丧失突变的患者患有丙酸血症，因为他们无法分解代谢丙酸酯，导致其有害积累。代谢性疾病的渗透率和表达能力都可以通过遗传背景来调节。但是，由于缺乏人类遗传学中罕见疾病的统计能力，因此很难确定这些疾病的修饰语。在这里，我们使用线虫秀丽隐杆线虫中丙酸血症模型以确定丙酸敏感性的遗传修饰因子。使用跨野生株的全基因组关联（GWA）映射，我们确定了与降低的丙酸敏感性相关的几个基因组区域。我们发现推定的葡萄糖醛酸糖基转移酶GLCT-3（人B3GAT的同系物）的自然变异部分解释了在这些基因组区间之一中丙酸敏感性的差异。我们证明了glct-3中功能丧失的等位基因使动物对丙酸的敏感性降低。此外，我们发现，Ç。线虫有glct的扩展基因家族，表明该家族成员的数量可能影响对过量丙酸酯的敏感性。我们的发现表明，与丙酸盐分解不直接相关的基因的自然变异可以调节丙酸盐敏感性。我们的研究提供了使用C的框架。秀丽隐杆线虫来表征遗传背景在人类先天性代谢错误模型中的作用。