MUT gene variants in patients with methylmalonic acidemia in Bangladeshi population and their distinguishing metabolic profiles

Abstract Methylmalonic acidemia (MMA) is a rare inborn error of organic acid metabolism presented with wide range of clinical features from mild to severe life-threatening conditions. It is caused mostly due to defective activity of the enzyme methylmalonyl-CoA mutase (MCM), which is encoded by the MUT gene. In this study we analyzed the clinical and biochemical features as well as mutation spectrum in the coding regions (exon 2–13) of the MUT gene and their adjacent intronic consensus splice sites in unrelated MMA patients and healthy individuals. We identified 14 mutations in the MUT gene among which two (c.856G > C and c.1676 + 15C > T) were not reported earlier. Bioinformatics tools were used to explore the molecular consequences of these 14 mutations on MCM activity and correlated these predictions to the phenotypic severities of the patients. Our analysis suggest that a novel mutation c.856G > C (p.E286Q) and a previously reported mutation c.1837C > T (R613C) may have disease causing effect and play important role in methylmalonic acidemia. In addition, we compared the profiles of 79 metabolic features (47 individual metabolite concentrations and 32 ratios) between the MMA patients and healthy controls. Although elevated levels of propionylcarnitine (C3) and ratio of propionylcarnitine (C3) to acetylcarnitine (C2) in blood are considered as the diagnostic features of MMA, this study could clearly distinguish between the MMA patients and the controls based on C3 levels only, but not C3/C2 in a statistically significant manner. In addition to C3, the ratio of argininosuccinic acid (ASA), argininosuccinic acid/arginine (ASA/Arg), and 3-hydroxyisovaleryl−/2-methyl-3-hydroxybutyryl-carnitine/propionylcarnitine (C5OH/C3) were clearly distinguishable between the groups with ≥2 fold changes in concentration.