IDENTIFICATION OF A MUTATION IN THE LOW-DENSITY-LIPOPROTEIN RECEPTOR GENE ASSOCIATED WITH RECESSIVE FAMILIAL HYPERCHOLESTEROLEMIA IN SWINE

Elevated blood plasma cholesterol (hypercholesterolemia) is a major ri sk factor for coronary artery disease (CAD) in humans, Genetic dissect ion of polygenic lipid and lipoprotein disorders in swine, a key anima l model for the study of familial hypercholesterolemia (FH) and CAD, l ed to the isolation of a monogenic subphenotype (FH-r), that is inheri ted in the recessive (r) manner, A genome scan mapped the FH-r locus c lose to the centromere of chromosome 2, Comparative mapping showed tha t this region shares homology with a part of human chromosome 19 that harbors the low density lipoprotein receptor (LDLR) locus, and therefo re suggested LDLR as the prime candidate gene for FH-r, Cloning and se quencing of hepatic LDLR cDNA from two FH-r/r and one normal (N/N) ani mals disclosed a single missense mutation (R84C) in a region that corr esponds to human exon 4, The C84 mutation cosegregates invariantly wit h hypercholesterolemia, which strongly suggests that this mutation is responsible for the observed hyperlipidemia. (C) 1998 Wiley-Liss, Inc.