Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type
Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type
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DOI：
10.1016/j.ymgme.2007.11.005
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发表时间：
2008-04-01
影响因子：
3.8
通讯作者：
Dionisi-Vici, Carlo
中科院分区：
文献类型：
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作者：
Nogueira, Celia;Aiello, Chiara;Dionisi-Vici, Carlo
甲基丙二酸尿症 (MMA) 和高胱氨酸尿症，cblC 型 (MIM 277400) 是维生素 B-12 最常见的先天性错误。最近对疾病基因 MMACHC 的鉴定已允许进行初步的基因型-表型相关性。我们研究了 24 名意大利和 17 名患有 cblC 缺陷的葡萄牙患者，以说明南欧人群的突变谱，并讨论突变鉴定对常规诊断程序的影响。由于代谢缺陷会提高同型半胱氨酸的血清水平，我们还测试了 MTHFR 中的变异（在同型半胱氨酸再甲基化途径中发挥关键作用）是否可以充当 cblC 缺陷的遗传修饰剂。我们发现 c.271 dupA（占我们队列中 MMA CH 等位基因的 55%）其次是 c.394C > T (16%) 和 c.331C > T (9%)频繁突变。在我们的研究中，我们还发现了一种新的突变（c.544T > C）。另一方面，MTHFR 基因型似乎并不影响 cblC 缺陷患者的发病年龄、临床表型和结果。这项研究表明，对早发形式最常见的 MMACH 突变（c.271dupA 和 c.331C > T）进行突变筛查似乎在患有 cblC 缺陷的南欧人群中具有较高的诊断率。尽管基因缺陷本身的识别并不能完全预测疾病出现的时间和严重程度，但我们的数据证实了分子检测的重要性，它可以为生育孩子的高风险夫妇提供准确的产前诊断。 (C) 2007 Elsevier Inc. 保留所有权利。
Methylmalonic aciduria (MMA) and homocystinuria, cblC type (MIM 277400) is the most frequent inborn error of vitamin B-12. The recent identification of the disease gene, MMACHC, has permitted preliminary genotype-phenotype correlations.We studied 24 Italian and 17 Portuguese patients with cblC defect to illustrate the spectrum of mutations in a southern European population and discuss the impact that mutation identification has on routine diagnostic procedures. Since the metabolic defect raises the serum levels of homocysteine, we also tested if variants in MTHFR-playing a key role in homocysteine remethylation pathway-could act as genetic modifier in cblC defect.We found that the c.271 dupA (accounting for 55% of the MMA CH alleles in our cohort) followed by c.394C > T (16%) and c.331C > T (9%) were the most frequent mutations. In our study we also identified a novel mutation (c.544T > C). On the other hand, the MTHFR genotype did not appear to influence age at onset, the clinical phenotype and outcome of patients with cblC defect.This study shows that mutation screening for the most common MMACH mutations occurring in early-onset forms (c.271dupA and c.331C > T) seems to have a high diagnostic yield in a southern European population with cblC defect. Although the identification of the gene defect per se does not predict completely time and severity of disease appearance, our data corroborate the importance of a molecular testing to offer accurate prenatal diagnosis to couples at high risk of having affected children. (C) 2007 Elsevier Inc. All rights reserved.