Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are relatively common lipid disorders caused by mutations in the low-density lipoprotein receptor (LDLR) and apolipoprotein B (apo B) genes, respectively. Molecular analysis at these loci was performed in eight New Zealand subjects with clinical features of heterozygous FH. Utilization of an in vitro lymphocyte receptor assay demonstrated normal receptor function in four patients, three of whom screened positive for the founder-type apo B mutation, R3500Q, causing FDB. Four patients with reduced LDLR function, consistent with heterozygous FH, revealed three previously documented mutations in exons 3 (W66X), 6 (C292Y) and 7 (G322S) of the LDLR gene and, a novel 2-bp deletion (TC or CT) after nucleotide 1204 (or 1205) in exon 9. The remaining patient was found to be FH/FDB negative after extensive mutation screening using both denaturing gradient gel electrophoresis and heteroduplex-single strand conformation polymorphism analysis. Haplotype analysis at the LDLR and apo B loci finally excluded the likelihood that mutations in these two genes underlie the FH phenotype in the molecularly uncharacterized New Zealand family originating from the United Kingdom. This family represents a valuable source of material for future genetic dissection of autosomal dominant hypercholesterolemia (ADH), shown to be a heterogeneous disease through molecular analysis.
Copyright 2000 Academic Press.