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

We have identified a mutation ( 2 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 re- gion binds Sp1 and collaborates with repeat 2 in the regula- tion of LDLR gene by sterols. To evaluate whether the mu- tation influenced the activity of the promoter, luciferase reporter plasmids containing 296 bp of the proximal pro- moter region were constructed. In transient transfection as- says in HepG2 cells, the mutation resulted in an 80% reduc- tion 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 2 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. Pocovi, and J. C. Rodriguez- Rey. A mutation ( 2 49C. T) in the promoter of the low den- sity lipoprotein receptor gene associated with familial hyperc- holesterolemia. J. Lipid Res. 2002. 43: 13-18.