A mutation (T-45C) in the promoter region of the low-density-lipoprotein (LDL)-receptor gene is associated with a mild clinical phenotype in a patient with heterozygous familial hypercholesterolaemia (FH)

Human Molecular Genetics
X M SunA K Soutar

Abstract

We have identified a rare mutation (T-45C) in the low density lipoprotein (LDL)-receptor gene in a Welsh patient with a clinical diagnosis of heterozygous familial hypercholesterolaemia (FH). The mutation is in the proximal Sp1 binding site in repeat 3 of the 42 bp region of the promoter required for sterol-dependent regulation of transcription, but the substituted nucleotide is not a strongly conserved base in the consensus sequence for Sp1 binding. Normal and mutant promoter fragments (from base -600 to -5) were linked to a luciferase reporter gene, and transient expression in COS cells showed that the mutation reduced transcriptional activity to approximately 43% of normal in the presence, and 25% in the absence of sterols in the medium. Competitive gel-shift mobility assays showed that the mutation reduced the binding affinity for transcription factor Sp1. Analysis of a neutral polymorphism in the LDL-receptor mRNA from the patient's lymphoblasts showed that expression of one allele was reduced. Since Southern blotting of genomic DNA and sequencing of the entire coding region of the LDL-R gene did not reveal any other potential defects, we infer that the T-45 C mutation is the underlying cause of hypercholesterolaemia in th...Continue Reading

Citations

Jul 13, 2007·European Journal of Human Genetics : EJHG·Andrew J P SmithSteve E Humphries
Aug 24, 1999·Nucleic Acids Research·S Philipsen, G Suske
Apr 29, 1998·Current Opinion in Lipidology·A K Soutar
Mar 14, 2007·Current Opinion in Lipidology·Sandra Pampín, José C Rodríguez-Rey
Sep 25, 2014·European Journal of Human Genetics : EJHG·Amna KhamisSteve E Humphries
Feb 9, 2017·Current Opinion in Lipidology·Mafalda BourbonEric J Sijbrands
Feb 17, 2000·Arteriosclerosis, Thrombosis, and Vascular Biology·I Leviev, R W James
Dec 31, 1997·The Journal of Biological Chemistry·D P WadeR Taramelli
Nov 4, 2004·Human Mutation·George V Z DedoussisJanine Genschel
Jan 1, 2014·International Journal of Molecular Medicine·Haibin ChenJinfa Jiang

❮ Previous
Next ❯

Related Concepts

Related Feeds

ApoE, Lipids & Cholesterol

Serum cholesterol, triglycerides, apolipoprotein B (APOB)-containing lipoproteins (very low-density lipoprotein (VLDL), immediate-density lipoprotein (IDL), and low-density lipoprotein (LDL), lipoprotein A (LPA)) and the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio are all connected in diseases. Here is the latest research.