Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese.
Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese.
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DOI：
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发表时间：
1994-10
影响因子：
3.6
通讯作者：
S. M. Morais;G. Wilkinson;J. Blaisdell;U. Meyer;K. Nakamura;J. Goldstein
中科院分区：
文献类型：
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作者：
S. M. Morais;G. Wilkinson;J. Blaisdell;U. Meyer;K. Nakamura;J. Goldstein
抗惊厥药物(S)-美苯妥因代谢的遗传多态性在人类中得到了很好的证明。不良代谢物表型的频率存在明显的种族差异，高加索人占2%-5%，亚洲人占18%-23%。我们最近报道，导致代谢产物表型不良的主要遗传缺陷是CYP2C19(CYP2C19m)外显子5的单碱基对突变，该突变约占日本人和高加索人缺陷等位基因的75%-83%。在本研究中，我们在日本的低代谢者中发现了一个新的突变(CYP2C19m2)，该突变包括在CYP2C19外显子4的636位鸟嘌呤到腺嘌呤的突变，该突变产生了一个过早的终止密码子。对7个不是先前描述的CYP2C19m缺陷(现命名为CYP2C19m1)纯合子的日本代谢不良者进行的基因分型表明，他们要么是新缺陷的纯合子(CYP2C19m2/CYP2C19m2)，要么是这两个缺陷的杂合子(CYP2C19m1/CYP2C19m2)。在日本弱代谢人群的34个等位基因中，有25个为CYP2C19m1，其余9个为CYP2C19m2。因此，CYP2C19m1和CYP2C19m2可100%解释日本现有的弱代谢物(34个等位基因)。相比之下，在9个高加索低代谢者中没有检测到CYP2C19m2缺陷(83%的可用低代谢者等位基因是CYP2C19m1)，这表明存在另一个尚未确定的突变。对两个日本不良代谢物先证者家系的遗传检测表明，CYP2C19m1和CYP2C19m2等位基因的共遗传符合不良代谢物表型的常染色体隐性遗传。
A genetic polymorphism in the metabolism of the anticonvulsant drug (S)-mephenytoin has been well documented in humans. There are marked interracial differences in the frequency of the poor metabolizer phenotype, which comprises 2-5% of Caucasian but 18-23% of Asian populations. We have recently reported that the principal genetic defect responsible for the poor metabolizer phenotype is a single-base pair mutation in exon 5 of CYP2C19 (CYP2C19m), which accounts for approximately 75-83% of the defective alleles in both Japanese and Caucasians subjects. In the present study, we have identified a new mutation (CYP2C19m2) in Japanese poor metabolizers, consisting of a guanine to adenine mutation at position 636 of exon 4 of CYP2C19, which creates a premature stop codon. Genotyping of seven Japanese poor metabolizers who were not homozygous for the previously described CYP2C19m defect (now designated CYP2C19m1) indicated that they were either homozygous for the new defect (CYP2C19m2/CYP2C19m2) or heterozygous (CYP2C19m1/CYP2C19m2) for the two defects. CYP2C19m1 accounts for 25 of 34 alleles in Japanese poor metabolizers, whereas CYP2C19m2 accounts for the remaining nine alleles. Hence, CYP2C19m1 and CYP2C19m2 explain 100% of the available Japanese poor metabolizers (34 alleles). In contrast, the CYP2C19m2 defect was not detected in nine Caucasian poor metabolizers (83% of available poor metabolizer alleles were CYP2C19m1), indicating the existence of another, as yet unidentified, mutation. Genetic testing of the families of two Japanese poor metabolizer probands showed that coinheritance of the CYP2C19m1 and CYP2C19m2 alleles was concordant with the autosomal recessive inheritance of the poor metabolizer phenotype.