大鼠STSL基因座：豆甾醇血症性高血压大鼠的特征、染色体定位及遗传变异
The rat STSL locus: characterization, chromosomal assignment, and genetic variations in sitosterolemic hypertensive rats.
作者信息
Yu Hongwei, Pandit Bhaswati, Klett Eric, Lee Mi-Hye, Lu Kangmo, Helou Khalil, Ikeda Ikuo, Egashira Nami, Sato Masao, Klein Richard, Batta Ashok, Salen Gerald, Patel Shailendra B
机构信息
Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, STR 541, 114 Doughty Street, Charleston, SC 29403, USA.
出版信息
BMC Cardiovasc Disord. 2003 Jun 3;3:4. doi: 10.1186/1471-2261-3-4.
BACKGROUND
Elevated plant sterol accumulation has been reported in the spontaneously hypertensive rat (SHR), the stroke-prone spontaneously hypertensive rat (SHRSP) and the Wistar-Kyoto (WKY) rat. Additionally, a blood pressure quantitative trait locus (QTL) has been mapped to rat chromosome 6 in a New Zealand genetically hypertensive rat strain (GH rat). ABCG5 and ABCG8 (encoding sterolin-1 and sterolin-2 respectively) have been shown to be responsible for causing sitosterolemia in humans. These genes are organized in a head-to-head configuration at the STSL locus on human chromosome 2p21.
METHODS
To investigate whether mutations in Abcg5 or Abcg8 exist in SHR, SHRSP, WKY and GH rats, we initiated a systematic search for the genetic variation in coding and non-coding region of Abcg5 and Abcg8 genes in these strains. We isolated the rat cDNAs for these genes and characterized the genomic structure and tissue expression patterns, using standard molecular biology techniques and FISH for chromosomal assignments.
RESULTS
Both rat Abcg5 and Abcg8 genes map to chromosome band 6q12. These genes span ~40 kb and contain 13 exons and 12 introns each, in a pattern identical to that of the STSL loci in mouse and man. Both Abcg5 and Abcg8 were expressed only in liver and intestine. Analyses of DNA from SHR, SHRSP, GH, WKY, Wistar, Wistar King A (WKA) and Brown Norway (BN) rat strains revealed a homozygous G to T substitution at nucleotide 1754, resulting in the coding change Gly583Cys in sterolin-1 only in rats that are both sitosterolemic and hypertensive (SHR, SHRSP and WKY).
CONCLUSIONS
The rat STSL locus maps to chromosome 6q12. A non-synonymous mutation in Abcg5, Gly583Cys, results in sitosterolemia in rat strains that are also hypertensive (WKY, SHR and SHRSP). Those rat strains that are hypertensive, but not sitosterolemic (e.g. GH rat) do not have mutations in Abcg5 or Abcg8. This mutation allows for expression and apparent apical targeting of Abcg5 protein in the intestine. These rat strains may therefore allow us to study the pathophysiological mechanisms involved in the human disease of sitosterolemia.
背景
自发性高血压大鼠（SHR）、易中风自发性高血压大鼠（SHRSP）和Wistar-Kyoto（WKY）大鼠中均有植物甾醇蓄积升高的报道。此外，在一种新西兰遗传性高血压大鼠品系（GH大鼠）中，已将一个血压数量性状基因座（QTL）定位到大鼠6号染色体上。ABCG5和ABCG8（分别编码甾醇转运蛋白1和甾醇转运蛋白2）已被证明是导致人类谷甾醇血症的原因。这些基因在人类2号染色体2p21的STSL基因座上以头对头的方式排列。
方法
为了研究SHR、SHRSP、WKY和GH大鼠中是否存在Abcg5或Abcg8突变，我们对这些品系中Abcg5和Abcg8基因的编码区和非编码区的遗传变异进行了系统搜索。我们分离了这些基因的大鼠cDNA，并使用标准分子生物学技术和荧光原位杂交（FISH）进行染色体定位，对基因组结构和组织表达模式进行了表征。
结果
大鼠Abcg5和Abcg8基因均定位于6号染色体带6q12。这些基因跨度约40kb，各包含13个外显子和12个内含子，其模式与小鼠和人类的STSL基因座相同。Abcg5和Abcg8仅在肝脏和肠道中表达。对SHR、SHRSP、GH、WKY、Wistar、Wistar King A（WKA）和Brown Norway（BN）大鼠品系的DNA分析显示，在核苷酸1754处存在纯合的G到T替换，仅在患有谷甾醇血症和高血压的大鼠（SHR、SHRSP和WKY）中导致甾醇转运蛋白1中的编码变化Gly583Cys。
结论
大鼠STSL基因座定位于6号染色体6q12。Abcg5中的一个非同义突变Gly583Cys导致同时患有高血压的大鼠品系（WKY、SHR和SHRSP）出现谷甾醇血症。那些患有高血压但没有谷甾醇血症的大鼠品系（如GH大鼠）在Abcg5或Abcg8中没有突变。这种突变允许Abcg5蛋白在肠道中表达并明显靶向顶端。因此，这些大鼠品系可能使我们能够研究人类谷甾醇血症疾病所涉及的病理生理机制。
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