Genetic variations of the ABC transporter gene ABCC3 in a Japanese population
Genetic variations of the ABC transporter gene ABCC3 in a Japanese population
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DOI：
10.2133/dmpk.22.129
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发表时间：
2007-01-01
影响因子：
2.1
通讯作者：
Sawada, Jun-ichi
中科院分区：
文献类型：
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作者：
Fukushima-Uesaka, Hirorni;Saito, Yoshiro;Sawada, Jun-ichi
多药耐药相关蛋白3（MRP 3）是一种ATP结合盒转运蛋白，由ABCC 3基因编码。MRP 3蛋白在几种组织中表达，作为结合和非结合底物的外排转运蛋白发挥作用。在这项研究中，31 ABCC 3外显子及其侧翼内含子的遗传变异进行了全面的筛选，在89个日本科目。共发现46个遗传变异，其中21个为新变异：8个位于5 '侧翼区，14个位于编码外显子（8个同义变异和6个非同义变异），24个位于内含子。在这46个变异中，发现5个新的非同义变异，2221 C>T（Gln 741 Stop）、2395 G>A（Val 799 Met）、2798_2799delAG（Gln 933 ArgfsX 64）、3657 C>A（Ser 1219 Arg）和4217 C>T（Thr 1406 Met）为杂合变异。Ser 1219 Arg的等位基因频率为0.011，其他四种变异的等位基因频率为0.006。Gln 741 Stop在密码子741处诱导终止密码子。Gln 933 ArgfsX 64引起密码子933处的移码，导致密码子997处的提前终止。两种变异均导致核苷酸结合结构域2的C-末端和所有区域中6个跨膜螺旋（从第12至第17个螺旋）的丢失。因此，假设两种变体蛋白质都是无活性的。这些数据提供了基本的和有用的信息，在日本的药物遗传学研究的MRP 3转运药物。
An ATP-binding cassette transporter, multidrug resistance-related protein 3 (MRP3), is encoded by the ABCC3 gene. The MRP3 protein is expressed in several tissues, and functions as an efflux transporter for conjugated as well as unconjugated substrates. In this study, the 31 ABCC3 exons and their flanking introns were comprehensively screened for genetic variations in 89 Japanese subjects. Forty-six genetic variations, including 21 novel ones, were found: 8 were located in the 5'-flanking region, 14 in the coding exons (8 synonymous and 6 nonsynonymous variations), and 24 in the introns. Of these 46 variations, five novel nonsynonymous variations, 2221C>T (Gln741Stop), 2395G>A (Val799Met), 2798_2799delAG (Gln933ArgfsX64), 3657C>A (Ser1219Arg), and 4217C>T (Thr1406Met), were found as heterozygous variations. The allele frequencies were 0.011 for Ser1219Arg and 0.006 for the other four variations. Gln741Stop induces a stop codon at codon 741. Gln933ArgfsX64 causes a frame-shift at codon 933, resulting in early termination at codon 997. Both variations result in loss of 6 transmembrane helices (from the 12th to 17th helices) in the C-terminus and all regions of nucleotide binding domain 2. Thus, both variant proteins are assumed to be inactive. These data provide fundamental and useful information for pharmacogenetic studies on MRP3-transported drugs in Japanese.