Determination of Autosomal Dominant or Recessive Methionine Adenosyltransferase I/III Deficiencies Based on Clinical and Molecular Studies
Determination of Autosomal Dominant or Recessive Methionine Adenosyltransferase I/III Deficiencies Based on Clinical and Molecular Studies
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DOI：
10.2119/molmed.2015.00254
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发表时间：
2016-01-01
影响因子：
5.7
通讯作者：
Lee, Beom Hee
中科院分区：
文献类型：
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作者：
Kim, Yoo-Mi;Kim, Ja Hye;Lee, Beom Hee
甲硫氨酸腺苷转移酶(MAT)I/III缺乏症可遗传为常染色体显性(AD)或隐性(AR)性状，在这些性状中已分别检测到单等位基因或双等位基因突变。虽然大多数患者的临床结果是良性的，但也有一些AR患者有神经功能障碍。在这里，我们描述了来自15个经新生儿筛查确认的无血缘关系的家系的16名患有MAT I/III缺乏症的韩国患者。10名先证者患有AD MAT I/III缺陷，6名先证者患有AR MAT I/III缺陷。AD组血浆蛋氨酸水平(145.7 mU/L比733.2 mU/L，P<0.05)和同型半胱氨酸水平(12.3mU/L比18.6 mU/L，P<0.05)均低于AR组。除了已报道的AD MAT1A突变p.Arg264His外，我们还发现了两个新的AD突变p.Arg249Gln和p.Gly280Arg。在AR类型中，发现了四个先前报道的突变和两个新的突变，即p.Arg163Trp和p.Tyr335*。定量基因组聚合酶链式反应(PCR)未发现外显子缺失。三维结构预测程序显示，AD型突变位于二聚体界面或底物结合部位，分别阻碍MAT I/III二聚或底物结合，而AR突变远离界面或底物结合部位。这些结果表明AD或AR mat I/III缺陷与患者的临床表现、底物水平和突变蛋白的结构特征有关，这对患者的神经治疗和遗传咨询具有重要意义。
Methionine adenosyltransferase (MAT) I/III deficiency can be inherited as autosomal dominant (AD) or as recessive (AR) traits in which mono- or biallelic MAT1A mutations have been identified, respectively. Although most patients have benign clinical outcomes, some with the AR form have neurological deficits. Here we describe 16 Korean patients with MAT I/III deficiency from 15 unrelated families identified by newborn screening. Ten probands had the AD MAT I/III deficiency, while six had AR MAT I/III deficiency. Plasma methionine (145.7 mu mol/L versus 733.2 mu mol/L, P < 0.05) and homocysteine levels (12.3 mu mol/L versus 18.6 mu mol/L, P < 0.05) were lower in the AD type than in AR type. In addition to the only reported AD MAT1A mutation, p.Arg264His, we identified two novel AD mutations, p.Arg249Gln and p.Gly280Arg. In the AR type, four previously reported and two novel mutations, p.Arg163Trp and p.Tyr335*, were identified. No exonic deletions were found by quantitative genomic polymerase chain reaction (PCR). Three-dimensional structural prediction programs indicated that the AD-type mutations were located on the dimer interface or in the substrate binding site, hindering MAT I/III dimerization or substrate binding, respectively, whereas the AR mutations were distant from the interface or substrate binding site. These results indicate that the AD or AR MAT I/III deficiency is correlated with clinical findings, substrate levels and structural features of the mutant proteins, which is important for the neurological management and genetic counseling of the patients.