Dantas Maria Fernanda, Suormala Terttu, Randolph Ann, Coelho David, Fowler Brian, Valle David, Baumgartner Matthias R
Division of Metabolism and Molecular Pediatrics, University Children's Hospital, Zurich, Switzerland.
Hum Mutat. 2005 Aug;26(2):164. doi: 10.1002/humu.9352.
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.
孤立性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疾病，似乎是基于串联质谱（TMS）的新生儿筛查项目中检测到的最常见的有机酸尿症。其表型多样，从伴有严重神经受累的新生儿发病到无症状的成年人。MCC是一种异聚体线粒体酶，由含生物素的α亚基和较小的β亚基组成，分别由MCCA和MCCB编码。我们报告了对28例MCC缺乏症先证者的突变分析，其中19例是通过TMS新生儿筛查检测到的无症状新生儿，9例有临床症状。10例在MCCA中有突变，18例在MCCB中有突变。我们鉴定出10个新的MCCA突变等位基因和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，并表明其中三个错义突变在MCC缺乏症细胞系中表达时会导致MCC活性严重降低。我们的数据表明基因型与表型之间没有明显的相关性，这表明除了MCC基因座的基因型外，其他因素对MCC缺乏症的表型有重大影响。
