FH‐Pyrgos: a novel mutation in the promoter (−45delT) of the low‐density lipoprotein receptor gene associated with familial hypercholesterolemia

In a patient with familial hypercholesterolemia (FH), we have identified a new mutation (−45delT) in repeat 3 of the low‐density lipoprotein receptor (LDLR) gene promoter. Analysis of a neutral polymorphism in the LDLR mRNA from the patient's white blood cells showed that the expression of one allele was significantly reduced, and cells have only 24% of LDLR activity by binding and uptake of DiI‐LDL. Transient transfection studies using a luciferase gene reporter revealed that the −45delT mutation considerably reduces the transcriptional activity of the LDLR promoter and strongly suggest that the mutation is the cause of the FH phenotype.

[1]  R. Galetto,et al.  A mutation (-49C>T) in the promoter of the low density lipoprotein receptor gene associated with familial hypercholesterolemia. , 2002, Journal of lipid research.

[2]  S E Humphries,et al.  Low-density lipoprotein receptor gene (LDLR) world-wide website in familial hypercholesterolaemia: update, new features and mutation analysis. , 2001, Atherosclerosis.

[3]  A. Marais,et al.  Mutation -59c-->t in repeat 2 of the LDL receptor promoter: reduction in transcriptional activity and possible allelic interaction in a South African family with familial hypercholesterolaemia. , 1999, Human molecular genetics.

[4]  R. Lafrenière,et al.  Improved detection of familial hypercholesterolemia by determining low density lipoprotein receptor expression in mitogen-induced proliferating lymphocytes. , 1998, Journal of lipid research.

[5]  G. Coetzee,et al.  A 3-basepair deletion in repeat 1 of the LDL receptor promoter reduces transcriptional activity in a South African Pedi. , 1998, Journal of lipid research.

[6]  Manfred Stuhrmann,et al.  LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis , 1998, Nucleic Acids Res..

[7]  P. Guldberg,et al.  Clinically applicable mutation screening in familial hypercholesterolemia , 1996, Human mutation.

[8]  A. Soutar,et al.  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). , 1995, Human molecular genetics.

[9]  O. Jänne,et al.  A single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[10]  T. Südhof,et al.  Sterol-dependent repression of low density lipoprotein receptor promoter mediated by 16-base pair sequence adjacent to binding site for transcription factor Sp1. , 1988, The Journal of biological chemistry.

[11]  T. Farag.  Familial hypercholesterolemia. , 1988, Journal of the Royal Society of Medicine.