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

IF 0.8 Q4 GENETICS & HEREDITY
Rokeya Begum , Abu Ashfaqur Sajib , A.B.M. Khademul Islam , Suprovath Kumar Sarker , Mohammad Sazzadul Islam , Narayan Saha , Kaiissar Mannoor , Firdausi Qadri , Sharif Akhteruzzaman
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引用次数: 1

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.

孟加拉国甲基丙二酸血症患者的MUT基因变异及其独特的代谢谱
甲基丙二酸血症(MMA)是一种罕见的先天性有机酸代谢错误,具有广泛的临床特征,从轻微到严重危及生命的疾病。它主要是由MUT基因编码的甲基丙二酰辅酶a (MCM)酶活性缺陷引起的。在这项研究中,我们分析了MMA患者和健康个体的临床和生化特征,以及MUT基因编码区(外显子2-13)及其相邻内含子一致剪接位点的突变谱。我们在MUT基因中发现了14个突变,其中两个(c.856G >C和C .1676 + 15C >T)之前没有报道。使用生物信息学工具来探索这14种突变对MCM活性的分子后果,并将这些预测与患者的表型严重程度联系起来。我们的分析表明,一种新的突变c.856G >C (p.E286Q)和先前报道的突变C . 1837c >T (R613C)可能具有致病作用,在甲基丙二酸血症中起重要作用。此外,我们还比较了MMA患者和健康对照之间的79种代谢特征(47种个体代谢物浓度和32种比率)。虽然血液中丙酰肉碱(C3)和丙酰肉碱(C3)与乙酰肉碱(C2)的比值升高被认为是MMA的诊断特征,但本研究仅根据C3水平可以明显区分MMA患者和对照组,但没有统计学意义上的C3/C2。除C3外,精氨酸琥珀酸(ASA)、精氨酸琥珀酸/精氨酸(ASA/Arg)和3-羟基异戊基- /2-甲基-3-羟基丁基-肉碱/丙酰肉碱(C5OH/C3)的比值在浓度变化≥2倍的组间差异明显。
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来源期刊
Meta Gene
Meta Gene Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
1.10
自引率
0.00%
发文量
20
期刊介绍: Meta Gene publishes meta-analysis, polymorphism and population study papers that are relevant to both human and non-human species. Examples include but are not limited to: (Relevant to human specimens): 1Meta-Analysis Papers - statistical reviews of the published literature of human genetic variation (typically linked to medical conditionals and/or congenital diseases) 2Genome Wide Association Studies (GWAS) - examination of large patient cohorts to identify common genetic factors that influence health and disease 3Human Genetics Papers - original studies describing new data on genetic variation in smaller patient populations 4Genetic Case Reports - short communications describing novel and in formative genetic mutations or chromosomal aberrations (e.g., probands) in very small demographic groups (e.g., family or unique ethnic group). (Relevant to non-human specimens): 1Small Genome Papers - Analysis of genetic variation in organelle genomes (e.g., mitochondrial DNA) 2Microbiota Papers - Analysis of microbiological variation through analysis of DNA sequencing in different biological environments 3Ecological Diversity Papers - Geographical distribution of genetic diversity of zoological or botanical species.
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