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.

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

ZULIANI, Giovanni;
1998

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.
1998
Peeters, Av; Kotze, Mj; Scholtz, Cl; DE WAAL, Lf; Rubinsztein, Dc; Coetzee, Ga; Zuliani, Giovanni; Streiff, R; Liu, Jw; VAN DER WESTHUYZEN, Dr...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/471742
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