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 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
AV
Division Human Genetics, Faculty of Medicine, University of Stellenbosch, Tygerberg, South Africa.
Kotze
M J
MJ
Scholtz
C L
CL
De Waal
L F
LF
Rubinsztein
D C
DC
Coetzee
G A
GA
Zuliani
G
G
Streiff
R
R
Liu
J
J
van der Westhuyzen
D R
DR
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
D011973:Receptors, LDL; D016329:Sp1 Transcription Factor; D004247:DNA