Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine
Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine
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DOI：
10.1097/00008571-200301000-00004
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发表时间：
2003-01-01
期刊：
影响因子：
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通讯作者：
Schuetz, EG
中科院分区：
文献类型：
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作者：
Zamber, CP;Lamba, JK;Schuetz, EG
本研究的目的是确定人类乳腺癌耐药蛋白（BCRP）的遗传变异程度。我们首先分析了来自人类肝脏和人类肠道的 BCRP cDNA 序列，并针对肠道 BCRP 的表达进行了表型分析。然后，我们使用代表 11 个不同种族群体的个体的 DNA 确定了所有已知编码单核苷酸多态性 (cSNP) 的频率。鉴定出 9 个 SNP，包括 4 个非同义 cSNP、3 个同义 cSNP 和 2 个内含子 SNP。在错义突变中，外显子 2 SNP (G34A) 导致 V12M 变化；外显子 5 SNP (C421A) 导致 Q141K 替换；外显子 6 SNP (A616C) 导致 1206L 氨基酸取代；外显子 15 SNP (A1768T) 导致 BCRP 蛋白发生 N590Y 变化。在研究人群中发现的两个最常见的多态性是 G34A 和 C421A 转换。不同人群中BCRP基因型和等位基因频率存在显着差异。通过实时聚合酶链反应对人小肠样本中的 BCRP mRNA 进行表型分析，并在同一个体的组织免疫印迹上分析 BCRP 蛋白。人肠道中 BCRP mRNA 的表达存在 78 倍的变化，BCRP 蛋白的表达存在显着变化。与表达 Lys(141) 等位基因的人相比，表达常见 Gln(141) 等位基因的人肠道 BCRP mRNA 和蛋白质的表达没有差异。因此，BCRP 常见的天然等位基因变异体已被鉴定，并且不影响人肠道中 BCRP mRNA 表达的个体间变异，但其对 BCRP 功能的影响仍有待测试。
The aim of this study was to identify the extent of genetic variability in breast cancer resistance protein (BCRP) in humans. We first analysed the sequence of BCRP cDNA from human livers and from human intestines phenotyped for expression of intestinal BCRP. We then determined the frequency of all known coding single nucleotide polymorphisms (cSNPs) using DNA from individuals representing 11 different ethnic populations. Nine SNPs including four non-synonymous and three synonymous cSNPs and two intronic SNPs were identified. Of the missense mutations, exon 2 SNP (G34A) resulted in a V12M change; exon 5 SNP (C421A) resulted in a Q141K substitution; exon 6 SNP (A616C) resulted in an 1206L amino acid substitution; and exon 15 SNP (A1768T) resulted in a N590Y change in the BCRP protein. The two most frequent polymorphisms identified in the human population studied were the G34A and C421A transitions. There was marked variation in BCRP genotypes and allele frequencies in the different populations. BCRP mRNA was phenotyped in human small bowel intestinal samples by real-time polymerase chain reaction and BCRP protein was analysed on immunoblots of tissue from the same individuals. There was a 78-fold variation in expression of BCRP mRNA and significant variation in BCRP protein expression in human intestine. Expression of intestinal BCRP mRNA and protein was not different between persons expressing the common Gln(141) allele compared to the Lys(141) allele. Thus, common natural allelic variants of BCRP have been identified, and did not influence interindividual variation in expression of BCRP mRNA in human intestine, but remain to be tested for their effect on BCRP function.