Familial defective apolipoprotein B-100 is caused by a substitution of adenine for guanine in exon 26 of the gene coding for apolipoprotein B, which results in the substitution of glutamine for arginine in the putative low-density lipoprotein—receptor binding domain of the mature protein. This amino acid substitution diminishes the binding capacity of the low-density lipiprotein particle for the low-density lipoprotein receptor, which in turn leads to an increase in levels of plasma total and low-density lipoprotein cholesterol.
To identify carriers of this mutation by means of molecular biology techniques in a large cohort of Dutch patients living in the Netherlands and in Canada with primary hypercholesterolemia, to establish the frequency of the disorder, and to investigate its clinical signs and symptoms and the response to cholesterol-lowering therapy.
A total of 1248 patients were screened, and the mutation was found in 18 patients who were initially all diagnosed as having familial hypercholesterolemia. Ten of 18 patients had tendon xanthomas or an arcus cornealis or both, and eight of 18 patients had angina or other evidence of coronary artery disease.
The disorder was clinically indistinguishable from familial hypercholesterolemia in terms of physical characteristics and lipoprotein measures. Response to lipid-lowering therapy with β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitors was similar to that reported in patients with familial hypercholesterolemia. The mutation was associated with a similar haplotype, which was also reported in other patients of Western European descent with familial defective apolipoprotein B100. This strongly suggests that the mutation has a common chromosomal background that originated in Western Europe.(Arch Intern Med. 1993;153:2349-2356)