A 3-basepair deletion in repeat 1 of the LDL receptor promoter reduces transcriptional activity in a South African Pedi

We have examined a naturally occurring muta- tion 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 posi- tion 2 92 (FH Pedi-2) in the distal Sp1 binding site in repeat 1 of the LDLR promoter. The patient carries a second mu- tant 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 fi- broblasts from the patient (5-15%), the rate of LDL recep- tor synthesis was markedly reduced to less than 20% of nor- mal. DNase I footprint analysis indicated that the 2 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 luci- ferase reporter gene demonstrated that the promoter frag- ment containing the 2 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 West- huyzen. A 3-basepair deletion in repeat 1 of the LDL recep- tor promoter reduces transcriptional activity in a South Afri- can Pedi. J. Lipid Res. 1998. 39: 1021-1024.