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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:e76.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

R3531C Mutation in the Apolipoprotein B Gene Is Not Sufficient to Cause Hypercholesterolemia

Jean-Pierre Rabès; Mathilde Varret; Martine Devillers; Philippe Aegerter; Ludovic Villéger; Michel Krempf; Claudine Junien; Catherine Boileau

From INSERM U383, the Hôpital Necker-Enfants Malades, Paris, France (J.-P.R., M.V., M.D., L.V., C.J., C.B.), Laboratoire de Biochimie et de Génétique Moléculaire (J.-P.R., C.J., C.B.) and Laboratoire de Biostatistique et d’Informatique Médicale (P.A.), Hôpital A. Paré, Boulogne, France, and Service d’Endocrinologie et de Nutrition, Hôpital Hôtel-Dieu, Nantes, France (M.K.).

Correspondence to C. Boileau, INSERM U383, Hôpital Necker-Enfants Malades, 149-161, rue de Sèvres 75743, Paris, Cedex 15, France. E-mail boileau{at}necker.fr

Abstract—Familial hypercholesterolemia and familial ligand-defective apolipoprotein B-100 (FDB) are dominantly inherited disorders leading to impaired low-density lipoprotein receptor (LDLR) and apolipoprotein B-100 (APOB) interaction, plasma LDL elevation, and hypercholesterolemia. We previously identified the first French FDB-R3531C proband, a woman with very high total cholesterol, in a group of type IIa hypercholesterolemic families. We report here the investigation of her family at large that revealed the total absence of cosegregation with hypercholesterolemia. Six of the 10 subjects heterozygous for the R3531C mutation had plasma cholesterol lower than the 97.5th percentile for their age and gender, and mean cholesterol levels were not significantly different between affected and unaffected persons. Furthermore, 2 family members with similar high LDL-cholesterol levels were not carriers of the R3531C substitution, suggesting the implication of another mutation. Segregation analysis of the LDLR gene revealed statistically significant genetic linkage with hypercholesterolemia, and analysis of the proband LDLR gene led to the identification of the 664 proline to leucine defective mutation and its detection in all 6 hypercholesterolemic-related members of this family. Therefore, our results show that the family presents with familial hypercholesterolemia and give evidence that the R3531C substitution in the APOB gene is not an allelic variant leading to FDB. Furthermore, thorough analysis of our data suggests that the APOB-R3531C mutation enhances the hypercholesterolemic effect of the LDLR-P664L defect, suggesting that it is a susceptibility mutation.

Key Words: hypercholesterolemia • apolipoprotein B • familial ligand-defective apolipoprotein B • low-density lipoprotein • familial hypercholesterolemia.