The rat STSL locus: Characterization, chromosomal assignment, and genetic variations in sitosterolemic hypertensive rats

Hongwei Yu, Bhaswati Pandit, Eric Klett, Mi Hye Lee, Kangmo Lu, Khalil Helou, Ikuo Ikeda, Nami Egashira, Masao Sato, Richard Klein, Ashok Batta, Gerald Salen, Shailendra B. Patel

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Abstract

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.

Original languageEnglish
Article number4
JournalBMC Cardiovascular Disorders
Volume3
DOIs
Publication statusPublished - Jun 3 2003

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Inbred SHR Rats
Mutation
Inbred WKY Rats
Genes
Intestines
Chromosomes
Phytosterols
Chromosomes, Human, Pair 6
Quantitative Trait Loci
Human Chromosomes
Protein Transport
Fluorescence In Situ Hybridization
New Zealand
Introns
Molecular Biology
Exons
Nucleotides
Complementary DNA
Stroke
Blood Pressure

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

The rat STSL locus : Characterization, chromosomal assignment, and genetic variations in sitosterolemic hypertensive rats. / 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.

In: BMC Cardiovascular Disorders, Vol. 3, 4, 03.06.2003.

Research output: Contribution to journalArticle

Yu, H, Pandit, B, Klett, E, Lee, MH, Lu, K, Helou, K, Ikeda, I, Egashira, N, Sato, M, Klein, R, Batta, A, Salen, G & Patel, SB 2003, 'The rat STSL locus: Characterization, chromosomal assignment, and genetic variations in sitosterolemic hypertensive rats', BMC Cardiovascular Disorders, vol. 3, 4. https://doi.org/10.1186/1471-2261-3-4
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. / The rat STSL locus : Characterization, chromosomal assignment, and genetic variations in sitosterolemic hypertensive rats. In: BMC Cardiovascular Disorders. 2003 ; Vol. 3.
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author = "Hongwei Yu and Bhaswati Pandit and Eric Klett and Lee, {Mi Hye} and Kangmo Lu and Khalil Helou and Ikuo Ikeda and Nami Egashira and Masao Sato and Richard Klein and Ashok Batta and Gerald Salen and Patel, {Shailendra B.}",
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AU - Pandit, Bhaswati

AU - Klett, Eric

AU - Lee, Mi Hye

AU - Lu, Kangmo

AU - Helou, Khalil

AU - Ikeda, Ikuo

AU - Egashira, Nami

AU - Sato, Masao

AU - Klein, Richard

AU - Batta, Ashok

AU - Salen, Gerald

AU - Patel, Shailendra B.

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N2 - 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.

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