Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia
Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia
复制标题
DOI：
10.1002/humu.20293
复制
发表时间：
2006-04-01
期刊：
影响因子：
3.9
通讯作者：
Matsubara, Y
中科院分区：
文献类型：
--
作者：
Kure, S;Kato, K;Matsubara, Y
非酮症高血糖(NKH)是一种以体液中甘氨酸蓄积和各种神经系统症状为特征的先天代谢错误。NKH是由GLDC、AMT和GCSH编码的三种特定成分的甘氨酸裂解多酶系统缺陷引起的。我们首次对69个家系进行了GLDC、AMT和GCSH突变的全面筛查(分别有56个、6个和7个新生儿、婴儿和晚发型NKH家系)。在75%的新生儿和83%的婴儿家庭中发现了GLDC或AMT突变，但在晚发型NKH中没有发现。本研究未发现GCSH突变。在36个家系中发现GLDC突变，在11个家系中发现AMT突变。在36个GLDC突变家系中的16个中，尽管对整个编码区进行了测序，但仅在一个等位基因中发现了突变。GLDC基因由25个外显子组成。32个GLDC错义突变中有7个集中在编码辅因子结合位点Lys754的外显子19上。在高加索人、东方人和黑人家庭中发现了涉及GLDC基因外显子1的大片段缺失。4个GLDC多态的单倍型分析提示外显子I缺失有多个来源。这项研究提供了迄今为止已知的NKH的遗传背景的全面图景。
Nonketotic hyperglycinemia (NKH) is an inborn error of metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. NKH is caused by deficiency of the glycine cleavage multi-enzyme system with three specific components encoded by GLDC, AMT, and GCSH. We undertook the first comprehensive screening for GLDC, AMT, and GCSH mutations in 69 families (56, six, and seven families with neonatal, infantile, and late-onset type NKH, respectively). GLDC or AMT mutations were identified in 75% of neonatal and 83% of infantile families, but not in late-onset type NKH. No GCSH mutation was identified in this study. GLDC mutations were identified in 36 families, and AMT mutations were detected in 11 families. In 16 of the 36 families with GLDC mutations, mutations were identified in only one allele despite sequencing of the entire coding regions. The GLDC gene consists of 25 exons. Seven of the 32 GLDC missense mutations were clustered in exon 19, which encodes the cofactor-binding site Lys754. A large deletion involving exon 1 of the GLDC gene was found in Caucasian, Oriental, and black families. Multiple origins of the exon I deletion were suggested by haplotype analysis with four GLDC polymorphisms. This study provides a comprehensive picture of the genetic background of NKH as it is known to date.