Comprehensive mutational screening of genes maintaining the glycine concentrations in the central nervous system

我们筛选了120个家庭血浆和/或脑脊液中甘氨酸浓度升高。通过对GLDC和AMT基因的筛查，我们在70%的患病家系中发现了致病突变。本研究的目的是对其余35个家系进行其他候选基因的突变筛查。作为影响胞外甘氨酸浓度的候选基因，我们选择了五个基因，GCSH、DLD、LPT、GLYT 1和GLYT 2基因。GLDC、AMT和DLD基因编码参与甘氨酸代谢的酶，而GLYT 1和GLYT 2基因编码甘氨酸的特异性转运蛋白。在GCSH基因，我们已经确定了一个碱基的变化，剪接受体的共识序列，AT，在内含子4。其他病例中未检测到GCSH突变。AT被替换成GT，这被认为是取消该内含子的剪接功能。患者被诊断为一过性高甘氨酸血症。另一个突变是LPT基因的错义突变，导致氨基酸由精氨酸替换为甘氨酸。精氨酸残基在其他香料中高度保守，表明其在进化上的重要性。在这一系列突变筛选中未检测到其他突变。我们的结论是，高甘氨酸血症可能是由其他基因比GLDC或AMT。

We have screened 120 families with elevated glycine concentration in plasma and/or cerebrospinal fluids. By the previous screening of GLDC and AMT genes, we identified the causative mutations in 70% of affected families. The purpose of this study is to perform the mutational screening of other candidate gene in the rest of the 35 families. As the candidate genes, which-affect the extracellular glycine concentrations we selected five genes, the GCSH, DLD, LPT, GLYT1, and GLYT2 genes. The GLDC, AMT, and DLD genes encode enzymes which involved in the glycine metabolism while GLYT1 and GLYT2 genes encode specific transporters of glycine. In the GCSH gene, we have identified a base change at the splicing acceptor consensus sequence, AT, in intron 4. No GCSH mutation was detected in other cases. The AT was substituted into GT, which is supposed to abolish the splicing function of this intron. The patients was given a diagnosis as having transient hyperglycinemia. The other mutation identified was missense mutation in LPT gene, which resulted in amino acid substitution form arginine to glycine. The arginine residue is highly conserved among the other spices, suggesting the evolutional importance. No other mutation have been detected in this series of the mutational screening. We concluded that hyperglycinemia can be caused by the other genes than GLDC or AMT.