Keyfi Fatemeh, Abbaszadegan Mohammad R, Sankian Mojtaba, Rolfs Arndt, Orolicki Slobodanka, Pournasrollah Mohammad, Alijanpour Morteza, Varasteh Abdolreza
Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran.
Division of Metabolic disorders, Pardis Clinical and Genetic Laboratory, Mashhad, Iran.
Mol Biol Rep. 2019 Feb;46(1):271-285. doi: 10.1007/s11033-018-4469-0. Epub 2019 Feb 2.
Methylmalonic acidemia (MMA), an inherited metabolic disease, results from genetic defects in methylmalonyl-CoA mutase or any of the proteins involved in adenosylcobalamin synthesis. This enzyme is classified into several complementation groups and genotypic classes. In this work we explain the biochemical, structural and genetic analysis of 25 MMA patients, from Iran. The diagnosis was established by the measurement of propionylcarnitine in blood using tandem mass spectrometry and confirmed using a gas chromatography-flame ionization detector. Using clinical, biochemical, structural and molecular analyses we identified 15 mut MMA, three cblA, one cblB, and four cblC-deficient patients. Among mutations identified in the MUT gene (MUT) only one, the c.1874A>C (p.D625A) variant, is likely a mut mutation. The remaining mutations are probably mut. Here, we present the first molecular analysis of MMA in Iranian patients and have identified eight novel mutations. Four novel mutations (p.D625A, p.R326G, p.V157F, p.F379L) were seen exclusively in patients from northern Iran. One novel splice site mutation (c.2125-3C>G) in MUT and two novel mutation (p.N225M and p.A99P) in the MMAA gene were associated with patients from eastern Iran. The rs184829210 SNP was recognized only in patients with the novel c.958G>A (p.A320T) mutation. This study confirms pathogenesis of deficient enzyme activity in MUT, MMAA, MMAB, and MMACHC as previous observations. These results could act as a basis for the performance of pharmacological therapies for increasing the activity of proteins derived from these mutations.
甲基丙二酸血症（MMA）是一种遗传性代谢疾病，由甲基丙二酰辅酶A变位酶或参与腺苷钴胺素合成的任何蛋白质的基因缺陷引起。这种酶被分为几个互补组和基因型类别。在这项工作中，我们解释了对来自伊朗的25名MMA患者的生化、结构和基因分析。通过串联质谱法测量血液中的丙酰肉碱进行诊断，并使用气相色谱 - 火焰离子化检测器进行确认。通过临床、生化、结构和分子分析，我们鉴定出15名mut MMA、3名cblA、1名cblB和4名cblC缺陷患者。在MUT基因（MUT）中鉴定出的突变中，只有一个c.1874A>C（p.D625A）变体可能是mut突变。其余突变可能是mut。在这里，我们展示了对伊朗患者MMA的首次分子分析，并鉴定出八个新突变。四个新突变（p.D625A、p.R326G、p.V157F、p.F379L）仅在伊朗北部的患者中出现。MUT基因中的一个新剪接位点突变（c.2125 - 3C>G）和MMAA基因中的两个新突变（p.N225M和p.A99P）与伊朗东部的患者相关。rs184829210 SNP仅在具有新的c.958G>A（p.A320T）突变的患者中被识别。这项研究证实了如先前观察到的MUT、MMAA、MMAB和MMACHC中酶活性缺陷的发病机制。这些结果可为开展旨在提高这些突变衍生蛋白质活性的药物治疗提供依据。
