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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:765-772.)
© 1995 American Heart Association, Inc.

Articles

FH Afrikaner-3 LDL Receptor Mutation Results in Defective LDL Receptors and Causes a Mild Form of Familial Hypercholesterolemia

J.F. Graadt van Roggen; D.R. van der Westhuyzen; G.A. Coetzee; A.D. Marais; K. Steyn; E. Langenhoven; M.J. Kotze

From the Medical Research Council (MRC)/University of Cape Town Research Unit for the Cell Biology of Atherosclerosis (J.F.G. van R., D.R. van der W., G.A.C.), Department of Medical Biochemistry, and the Department of Medicine (A.D.M.), University of Cape Town, Cape Town, the MRC Division for Chronic Diseases of Lifestyle (K.S.), Tygerberg, and the Department of Human Genetics (E.L., M.J.K.), Faculty of Medicine, University of Stellenbosch, Tygerberg, South Africa.

Correspondence to D.R. van der Westhuyzen, UCT/MRC Research Unit for the Cell Biology of Atherosclerosis, Department of Medical Biochemistry, UCT Medical School, Observatory 7925, Cape Town, South Africa.

Abstract Three founder-related gene mutations (FH Afrikaner-1, -2, and -3) that affect the LDL receptor are responsible for 90% of the familial hypercholesterolemia (FH) in South African Afrikaners. Patients heterozygous for the FH Afrikaner-1 (FH1) mutation, which results in receptors having 20% of normal receptor activity, have significantly lower plasma cholesterol levels and milder clinical symptoms than heterozygotes with the FH Afrikaner-2 mutation, which completely abolishes LDL receptor activity. In this study we re-created the FH3 mutation (Asp₁₅₄Asn) in exon 4 by site-directed mutagenesis and analyzed the expression of the mutant receptors in Chinese hamster ovary cells. The mutation resulted in the formation of LDL receptors that are markedly defective in their ability to bind LDL, whereas binding of apoE-containing ß-VLDL is less affected. The mutant receptors are poorly expressed on the cell surface as a result of significant degradation of receptor precursors. The plasma cholesterol levels of 31 FH3 heterozygotes were similar to FH1 heterozygotes but significantly lower than FH2 heterozygotes. The FH1 and FH3 heterozygotes also tended to be less severely affected clinically (by coronary heart disease and xanthomata) than FH2 patients. This study demonstrates that mutational heterogeneity in the LDL receptor gene influences the phenotypic expression of heterozygous FH and that severity of expression correlates with the activity of the LDL receptor measured in vitro. The results further indicate that knowledge of the specific mutation underlying FH in heterozygotes is valuable in determining the potential risk of premature atherosclerosis and should influence the clinical management of FH patients.

Key Words: familial hypercholesterolemia • LDL receptor • founder • cholesterol

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