出版社：American Society for Biochemistry and Molecular Biology
摘要：We have examined a naturally occurring mutation in the promoter region of the low density lipoprotein receptor (LDLR) gene of a South African Black patient with a clinical diagnosis of familial hypercholesterolemia (FH). The mutation constitutes a 3-bp deletion at nucleotide position -92 (FH Pedi-2) in the distal Sp1 binding site in repeat 1 of the LDLR promoter. The patient carries a second mutant LDLR allele containing a 1-bp deletion in exon 2 (FH Pedi-1) that gives rise to a frameshift mutation. Consistent with low receptor activity previously observed in cultured fibroblasts from the patient (5–15%), the rate of LDL receptor synthesis was markedly reduced to less than 20% of normal. DNase I footprint analysis indicated that the -92 mutation abolished binding of Sp1 to repeat 1 in the LDLR promoter. Transcription studies in transfected cells using normal and mutant promoter fragments linked to a luciferase reporter gene demonstrated that the promoter fragment containing the -92 mutation had approximately 10% of normal promoter activity. These findings indicate that the distal Sp1 binding site is essential for maximal activity of the normal intact LDLR promoter.— Peeters, A. V., M. J. Kotze, C. L. Scholtz, L. F. De Waal, D. C. Rubinsztein, G. A. Coetzee, G. Zuliani, R. Streiff, J. Liu, and D. R. van der Westhuyzen. A 3-basepair deletion in repeat 1 of the LDL receptor promoter reduces transcriptional activity in a South African Pedi. J. Lipid Res. 1998. 39: 1021–1024.
