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Journal of Lipid Research, Vol. 43, 13-18, January 2002
Copyright © 2002 by Lipid Research, Inc.

A mutation (-49C>T) in the promoter of the low density lipoprotein receptor gene associated with familial hypercholesterolemia

Correspondence to: José C. Rodríguez-Rey, To whom correspondence should be addressed. e-mail address: rodriguj@unican.es

We have identified a mutation (-49C>T) in the low-density lipoprotein receptor (LDLR) gene in a Spanish familial hypercholesterolemia (FH) patient. The mutation maps within repeat 3 of the LDLR gene promoter. This region binds Sp1 and collaborates with repeat 2 in the regulation of LDLR gene by sterols. To evaluate whether the mutation influenced the activity of the promoter, luciferase reporter plasmids containing 296 bp of the proximal promoter region were constructed. In transient transfection assays in HepG2 cells, the mutation resulted in an 80% reduction of promoter activity. Also, gel-shift assays demonstrated that the mutation severely affects Sp1 binding. However, the mutated promoter still retains the ability to respond to low sterol concentrations. As the analysis of the LDLR gene did not reveal any other changes, we conclude that the -49C>T mutation is the cause of FH in the patient. The analysis of the proband's pedigree indicated that not all the members of the family having the mutation disclose a FH phenotype.

These results support the view that factors other than the presence of the mutation are important in the determination of the clinical phenotype in FH. — Mozas P., R. Galetto, M. Albajar, E. Ros, M. Pocoví, and J. C. Rodríguez-Rey. A mutation (-49C>T) in the promoter of the low density lipoprotein receptor gene associated with familial hypercholesterolemia. J. Lipid Res. 2002. 43: 13–18.

Supplementary key words: gene expression, familial hypercholesterolemia, deoxyribonucleic acid, fetal bovine serum, low-density lipoprotein receptor gene

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