PHENOTYPIC-EXPRESSION IN DOUBLE HETEROZYGOTES FOR FAMILIAL HYPERCHOLESTEROLEMIA AND FAMILIAL DEFECTIVE APOLIPOPROTEIN B-100

Variability in the expression of monogenic lipid disorders may be obse rved in patients carrying the same DNA mutation, suggesting possible g enetic or environmental interactions. Our objective was to investigate the genotype phenotype relationships in two unrelated French patients with an aggravated expression of a dominantly inherited hypercholeste rolemia. In probands, segregation analysis complemented by DNA sequenc ing identified heterozygous defective alleles and mutations on two non allelic loci for two monogenic lipid disorders: familial hypercholeste rolemia at the low density lipoprotein (LDL) receptor locus and famili al defective apolipoprotein B-100 at the locus encoding its ligand, ap olipoprotein B-100. The LDL-receptor missense mutations had been repor ted in French Canadians. The apolipoprotein B mutation was the Arg3500 Gln founder mutation in Northern Europe. Probands had an unusual pheno type of aggravated hypercholesterolemia that was complicated with prem ature coronary arterial disease, although remaining responsive to lipi d-lowering drugs. This phenotype was distinct from that observed in th eir heterozygous relatives and distinct from those observed in FH or F DB homozygotes. These cases refer to a new class of patients with dige nic lipid disorders, defined by specific clinical features that result from the combined effects of two independent loci. Moreover, the obse rved phenotype of aggravated hypercholesterolemia gives further eviden ce that receptor and ligand play distinct roles in regulating LDL meta bolism. Although uncommon, these cases give insight into the molecular mechanisms that underly the clinical variability of inherited hyperch olesterolemia. (C) 1996 Wiley-Liss, Inc.