Janosík Miroslav, Sokolová Jitka, Janosíková Bohumila, Krijt Jakub, Klatovská Veronika, Kozich Viktor
Institute of Inherited Metabolic Disorders, Charles University in Prague-1st Faculty of Medicine, Prague, Czech Republic.
J Pediatr. 2009 Mar;154(3):431-7. doi: 10.1016/j.jpeds.2008.09.015. Epub 2008 Oct 31.
To estimate the frequency of the cystathionine beta-synthase deficiency caused by c.1105C>T mutation in Central Europe compared to Norway, and to examine the pathogenicity of the corresponding p.R369C mutant enzyme.
Mutation c.1105C>T was analyzed in 600 anonymous Czech newborn blood spots. Catalytic activity and quaternary structure of the p.R369C mutant was evaluated after expression in 2 cellular systems.
Population frequency of the c.1105C>T mutation was 0.005, predicting the birth prevalence of homocystinuria of 1:40000, which increased to 1:15500 in a model including 10 additional mutations. In Escherichia coli the p.R369C mutant misfolded, and its activity was severely reduced, and expression in Chinese hamster ovary cells enabled proper folding with activity decreased to 63% of the wild-type enzyme. This decreased activity was not due to impaired K(m) for both substrates but resulted from V(max) lowered to 55% of the normal cystathionine beta-synthase enzyme.
The c.1105C>T (p.R369C) allele is common also in the Czech population. Although the p.R369C mutation impairs folding and decreases velocity of the enzymatic reaction, our data are congruent with rather mild clinical phenotype in homozygotes or compound heterozygotes carrying this mutation.
与挪威相比，估计中欧地区由c.1105C>T突变导致的胱硫醚β-合酶缺乏症的发生频率，并检测相应的p.R369C突变酶的致病性。
对600份匿名的捷克新生儿血斑样本分析c.1105C>T突变。在2种细胞体系中表达后，评估p.R369C突变体的催化活性和四级结构。
c.1105C>T突变的人群频率为0.005，预测同型胱氨酸尿症的出生患病率为1:40000，在包含另外10种突变的模型中，这一患病率增至1:15500。在大肠杆菌中，p.R369C突变体错误折叠，其活性严重降低，而在中国仓鼠卵巢细胞中的表达使该突变体能够正确折叠，但其活性降至野生型酶的63%。活性降低并非由于两种底物的米氏常数（Km）受损，而是由于最大反应速度（Vmax）降至正常胱硫醚β-合酶的55%。
c.1105C>T（p.R369C）等位基因在捷克人群中也很常见。虽然p.R369C突变会损害折叠并降低酶促反应速度，但我们的数据与携带该突变的纯合子或复合杂合子中相对较轻的临床表型相符。
