title: A missense mutation in the Abcg5 gene causes phytosterolemia in SHR, stroke-prone SHR, and WKY rats.
abstract: Sitosterolemia is an autosomal recessive disorder caused by mutations in the ABCG5 or ABCG8 half-transporter genes. These mutations disrupt the mechanism that distinguishes between absorbed sterols and is most prominently characterized by hyperabsorption and impaired biliary elimination of dietary plant sterols. Sitosterolemia patients retain 15-20% of dietary plant sterols, whereas normal individuals absorb less than 1-5%. Normotensive Wistar Kyoto inbred (WKY inbred), spontaneously hypertensive rat (SHR), and stroke-prone spontaneously hypertensive rat (SHRSP) strains also display increased absorption and decreased elimination of dietary plant sterols. To determine if the genes responsible for sitosterolemia in humans are also responsible for phytosterolemia in rats, we sequenced the Abcg5 and Abcg8 genes in WKY inbred, SHR, and SHRSP rat strains. All three strains possessed a homozygous guanine-to-thymine transversion in exon 12 of the Abcg5 gene that results in the substitution of a conserved glycine residue for a cysteine amino acid in the extracellular loop between the fifth and sixth membrane-spanning domains of the ATP binding cassette half-transporter, sterolin-1. The identification of this naturally occurring mutation confirms that these rat strains are important animal models of sitosterolemia in which to study the mechanisms of sterol trafficking.
authors.affiliation: Nutrition Research Division, Food Directorate, Health Products and Food Branch, Health Canada, Banting Research Centre, Ottawa, Ontario, Canada. kylie_scoggan@hc-sc.gc.ca
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Scoggan
authors.forename: Heidi
authors.initials: H
authors.lastname: Gruber
authors.forename: Katherine
authors.initials: K
authors.lastname: Lariviere
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons; D015870:Gene Expression; D005796:Genes / Q000235:genetics; D007438:Introns; D008074:Lipoproteins / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010840:Phytosterols / Q000097:blood*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011913:Rats, Inbred BB; D011918:Rats, Inbred SHR / Q000235:genetics*; D011921:Rats, Inbred WKY / Q000235:genetics*; D017207:Rats, Sprague-Dawley; D017386:Sequence Homology, Amino Acid; D012855:Sitosterols / Q000097:blood
chemical_list: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; C480692:Abcg5 protein, rat; C480693:Abcg8 protein, rat; D008074:Lipoproteins; D010840:Phytosterols; D012333:RNA, Messenger; D012855:Sitosterols