title: A 3-basepair deletion in repeat 1 of the LDL receptor promoter reduces transcriptional activity in a South African Pedi.
abstract: 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.
authors.affiliation: Division Human Genetics, Faculty of Medicine, University of Stellenbosch, Tygerberg, South Africa.
authors.forename: A V
authors.initials: AV
authors.lastname: Peeters
authors.forename: M J
authors.initials: MJ
authors.lastname: Kotze
authors.forename: C L
authors.initials: CL
authors.lastname: Scholtz
authors.forename: L F
authors.initials: LF
authors.lastname: De Waal
authors.forename: D C
authors.initials: DC
authors.lastname: Rubinsztein
authors.forename: G A
authors.initials: GA
authors.lastname: Coetzee
authors.forename: G
authors.initials: G
authors.lastname: Zuliani
authors.forename: R
authors.initials: R
authors.lastname: Streiff
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: D R
authors.initials: DR
authors.lastname: van der Westhuyzen
mesh_terms: D001161:Arteriosclerosis / Q000235:genetics; D044383:Black People / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D018983:DNA Footprinting; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics; D008297:Male; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000235:genetics*; D017384:Sequence Deletion; D013019:South Africa; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation; D014973:Xanthomatosis / Q000235:genetics
chemical_list: D011973:Receptors, LDL; D016329:Sp1 Transcription Factor; D004247:DNA