3-Methylcrotonyl-CoA carboxylase deficiency: mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening.
3-Methylcrotonyl-CoA carboxylase deficiency: mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening.
复制标题
DOI：
10.1002/humu.9352
复制
发表时间：
2005-08-01
期刊：
影响因子：
3.9
通讯作者：
Baumgartner, Matthias R
中科院分区：
文献类型：
--
作者：
Dantas, Maria Fernanda;Suormala, Terttu;Baumgartner, Matthias R
孤立的3-甲基巴豆酰辅酶A羧化酶（MCC）缺乏症是一种常染色体隐性遗传疾病，似乎是最常见的有机酸尿症检测串联质谱（TMS）为基础的新生儿筛查计划。表型是可变的，从新生儿发病与严重的神经系统受累到无症状的成人。MCC是一种异聚体线粒体酶，由含有α亚基和较小β亚基的生物素组成，分别由MCCA和MCCB编码。我们报告了28例MCC缺陷先证者的突变分析，其中19例是经颅磁刺激新生儿筛查发现的无症状新生儿，9例有临床症状。10例MCCA突变，18例MCCB突变。我们确定了10个新的MCCA和14个新的MCCB突变等位基因，包括错义，无义，移码和剪接位点突变，并表明三个错义突变导致MCC活性严重下降时，在MCC缺陷细胞系中表达。我们的数据表明，基因型和表型之间没有明确的相关性，表明在MCC基因座的基因型以外的因素有一个主要的影响表型MCC缺乏症。
Isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder that appears to be the most frequent organic aciduria detected in tandem mass spectrometry (TMS)-based neonatal screening programs. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. MCC is a heteromeric mitochondrial enzyme composed of biotin containing alpha subunits and smaller beta subunits, encoded by MCCA and MCCB, respectively. We report mutation analysis in 28 MCC-deficient probands, 19 of whom were asymptomatic newborns detected by TMS newborn screening, and nine presented with clinical symptoms. Ten have mutations in MCCA, and 18 in MCCB. We identified 10 novel MCCA and 14 novel MCCB mutant alleles including missense, nonsense, frameshift and splice site mutations, and show that three of the missense mutations result in severely decreased MCC activity when expressed in MCC-deficient cell lines. Our data demonstrate no clear correlation between genotype and phenotype suggesting that factors other than the genotype at the MCC loci have a major influence on the phenotype of MCC deficiency.