title: Identification of a mutation in the low density lipoprotein receptor gene associated with recessive familial hypercholesterolemia in swine.
abstract: Elevated blood plasma cholesterol (hypercholesterolemia) is a major risk factor for coronary artery disease (CAD) in humans. Genetic dissection of polygenic lipid and lipoprotein disorders in swine, a key animal model for the study of familial hypercholesterolemia (FH) and CAD, led to the isolation of a monogenic subphenotype (FH-r), that is inherited in the recessive (r) manner. A genome scan mapped the FH-r locus close to the centromere of chromosome 2. Comparative mapping showed that this region shares homology with a part of human chromosome 19 that harbors the low density lipoprotein receptor (LDLR) locus, and therefore suggested LDLR as the prime candidate gene for FH-r. Cloning and sequencing of hepatic LDLR cDNA from two FH-r/r and one normal (N/N) animals disclosed a single missense mutation (R84C) in a region that corresponds to human exon 4. The C84 mutation cosegregates invariantly with hypercholesterolemia, which strongly suggests that this mutation is responsible for the observed hyperlipidemia.
authors.affiliation: Department of Genetics, University of Wisconsin, Madison 53706-1205, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hasler-Rapacz
authors.forename: H
authors.initials: H
authors.lastname: Ellegren
authors.forename: A K
authors.initials: AK
authors.lastname: Fridolfsson
authors.forename: B
authors.initials: B
authors.lastname: Kirkpatrick
authors.forename: S
authors.initials: S
authors.lastname: Kirk
authors.forename: L
authors.initials: L
authors.lastname: Andersson
authors.forename: J
authors.initials: J
authors.lastname: Rapacz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D005808:Genes, Recessive; D008040:Genetic Linkage; D006720:Homozygote; D006937:Hypercholesterolemia / Q000235:genetics* / Q000662:veterinary*; D008540:Meiosis; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011973:Receptors, LDL / Q000737:chemistry / Q000235:genetics*; D013552:Swine; D013553:Swine Diseases / Q000235:genetics*
chemical_list: D011973:Receptors, LDL