ASSOCIATION OF AN EXON-3 MUTATION (TRP66-]GLY) OF THE LDL RECEPTOR WITH VARIABLE EXPRESSION OF FAMILIAL HYPERCHOLESTEROLEMIA IN A FRENCH-CANADIAN FAMILY

The ligand-binding domain of low-density lipoprotein (LDL) is composed of seven 40-amino-acid repeats encoded by exons 2-6. Previous studies identified a missense mutation in codon 66 of exon 3, which resulted in the production of LDL receptor protein that is not processed to its mature form. In the current investigation, we documented the presence of two identical mutant LDL receptor alleles (Trp(66) --> Gly) in two familial hypercholesterolemia (FH) probands, II-1 and II-2, associate d with markedly elevated plasma LDL cholesterol (17.22 +/- 0.78 and 11 .95 +/- 0.24 mmol/liter, respectively). Functional assays of their fib roblast LDL receptor showed inefficient binding (39 and 50%), internal ization (33 and 37%), and degradation (32 and 37%) compared with contr ols. The contribution of the apo B gene to variation in LDL levels was virtually eliminated given the normal ligand interaction with cell su rface receptors and the absence of the mutation occurring in codon 350 0 of the apo B gene. Similarly, the homozygous apo E(3)/E(3) wildtype phenotype excluded any genetic contribution of apo E to the lipoprotei n abnormalities. Furthermore, the LPL mutations commonly observed in F rench Canadians could not account for the observed lipid alterations. Several alterations in lipoprotein composition characterized VLDL, IDL , LDL, HDL(2), and HDL(3) fractions. Moreover, defective intestinal fa t transport was observed in both probands (II-1 and II-2). Thus, the d isturbance of lipoprotein concentration, composition, size, and metabo lism may in part be related to the exon 3 mutation (Trp(66) --> Gly) o f the LDL receptor gene. The biochemical phenotype was more severe in the father (I-1) than in the mother (I-2), and in the younger homozygo us proband (II-1) than in the older (II-2). The greater severity was a ssociated with a higher LDL cholesterol/HDL cholesterol ratio. Whether the differences between the two probands are due to polygenic factors or to a metabolic consequence of a major nonallelic trait is unknown. Nevertheless, the present biochemical findings stress the extent of t he lipid abnormalities associated with homozygous FH and the importanc e of the phenotypic variability encountered even among subjects carryi ng the same mutation. (C) 1997 Academic Press.