Heinken Almut, Awada Hussein, Zanotelli Vito R T, Froese D Sean, Guéant-Rodriguez Rosa-Maria, Guéant Jean-Louis
UMRS Inserm 1256 nGERE (Nutrition-Genetics-Environmental Risks), Institute of Medical Research (Pôle BMS), University of Lorraine, Nancy, France.
Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, University of Zürich, Zürich, Switzerland.
J Inherit Metab Dis. 2025 Sep;48(5):e70077. doi: 10.1002/jimd.70077.
Cobalamin (vitamin B12) is an essential cofactor for two human enzymes, methionine synthase and methylmalonyl-CoA mutase. Inborn errors of cobalamin metabolism (IECMs) are inherited genetic defects resulting in improper transport, modification, or utilization of cobalamin and include inherited methylmalonic acidurias, a group of IECMs most frequently caused by a defect in the methylmalonyl-CoA mutase enzyme. Here, we performed genome-scale modeling of IECMs to gain insight into their metabolic perturbations. First, we simulated deficiencies in 11 IECM-related genes and demonstrated that they cluster based on impaired metabolic pathways. Next, we leveraged RNA sequencing data from fibroblasts of 202 individuals with methylmalonic aciduria and 19 unaffected controls to construct and interrogate personalized metabolic models. Finally, we analyzed fluxes differing between patients depending on reported symptom presentation. Our findings reveal that (i) metabolic pathways including fatty acid metabolism and heme biosynthesis have reduced flux in IECMs, (ii) in personalized simulations, succinate and fumarate production and heme biosynthesis are impaired, especially in methylmalonyl-CoA mutase deficiency, (iii) one-carbon metabolism reactions such as serine hydroxymethyltransferase and folylglutamate synthase have reduced flux in all individuals with methylmalonic aciduria, and (iv) specific metabolic pathways are up- or down-regulated according to symptoms, including failure to thrive and hematological abnormalities, and treatments, such as antibiotics and protein restriction. Overall, our study delineates metabolic pathways perturbed in IECMs. In future applications, our modeling framework could be applied to other rare genetic diseases or used to predict personalized therapeutic or dietary interventions.
钴胺素（维生素B12）是两种人体酶——甲硫氨酸合酶和甲基丙二酰辅酶A变位酶的必需辅因子。钴胺素代谢的先天性错误（IECMs）是遗传性基因缺陷，导致钴胺素的转运、修饰或利用不当，包括遗传性甲基丙二酸尿症，这是一组最常由甲基丙二酰辅酶A变位酶缺陷引起的IECMs。在这里，我们对IECMs进行了全基因组规模建模，以深入了解其代谢紊乱情况。首先，我们模拟了11个与IECM相关基因的缺陷，并证明它们根据受损的代谢途径聚类。接下来，我们利用来自202名甲基丙二酸尿症患者和19名未受影响对照的成纤维细胞的RNA测序数据，构建并研究个性化代谢模型。最后，我们分析了根据报告的症状表现患者之间不同的通量。我们的研究结果表明：（i）包括脂肪酸代谢和血红素生物合成在内的代谢途径在IECMs中通量降低；（ii）在个性化模拟中，琥珀酸和富马酸的产生以及血红素生物合成受损，尤其是在甲基丙二酰辅酶A变位酶缺乏症中；（iii）丝氨酸羟甲基转移酶和叶酰谷氨酸合酶等一碳代谢反应在所有甲基丙二酸尿症患者中通量降低；（iv）特定的代谢途径根据症状（包括生长发育不良和血液学异常）以及治疗方法（如抗生素和蛋白质限制）上调或下调。总体而言，我们的研究描绘了IECMs中受到干扰的代谢途径。在未来的应用中，我们的建模框架可应用于其他罕见遗传疾病，或用于预测个性化治疗或饮食干预措施。
