| Summary: | <p>Abstract</p> <p>Background</p> <p>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 <it>STSL </it>locus on human chromosome 2p21.</p> <p>Methods</p> <p>To investigate whether mutations in <it>Abcg5</it> or <it>Abcg8</it> exist in SHR, SHRSP, WKY and GH rats, we initiated a systematic search for the genetic variation in coding and non-coding region of <it>Abcg5</it> and <it>Abcg8</it> 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.</p> <p>Results</p> <p>Both rat <it>Abcg5</it> and <it>Abcg8</it> 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 <it>STSL </it>loci in mouse and man. Both <it>Abcg5</it> and <it>Abcg8</it> 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).</p> <p>Conclusions</p> <p>The rat <it>STSL </it>locus maps to chromosome 6q12. A non-synonymous mutation in <it>Abcg5</it>, 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 <it>Abcg5 </it>or <it>Abcg8</it>. This mutation allows for expression and apparent apical targeting of <it>Abcg5</it> protein in the intestine. These rat strains may therefore allow us to study the pathophysiological mechanisms involved in the human disease of sitosterolemia.</p>
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