DETECTION OF FAMILIAL DEFECTIVE APOLIPOPROTEIN B-100 AMONG PATIENTS CLINICALLY DIAGNOSED WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA INMARITIME CANADA

Familial defective apolipoprotein B-100 (FDB) is a genetic disorder re sulting from a mutation in the apolipoprotein B-100 (apo B-100) gene, most frequently at position 3500, in which arginine is substituted for glutamine in the mature protein. This mutation drastically decreases the affinity of the mutant apo B-100 particle for the low-density lipo protein (LDL) receptor, and hence decreases the clearance of cholester ol from the circulation. Familial hypercholesterolemia (FH), also a di sorder of lipid metabolism, results from mutations in the gene for the LDL receptor. Both FDB and heterozygous FH occur at approximately the same frequency (1 in 500) among Caucasians and both produce clinical symptoms and signs that can be indistinguishable. Polymerase chain rea ction (PCR) amplification and subsequent restriction analysis have bee n used to detect the substitution at codon 3500 in the apo B-100 gene using mutagenic PCR primers. At least one proband from 10 unrelated fa milies with a history of hypercholesterolemia was screened by mutageni c PCR for FDB. Only one of 10 patients demonstrated the mutation for F DB. The mutant apo B-100 allele was shown to segregate with other clin ically affected family members. These results demonstrate that molecul ar analysis is essential to distinguish between FDB and heterozygous F H in hypercholesterolemic families.