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A functional mutation in the LDLR promoter (−139C>G) in a patient with familial hypercholesterolemia

Smith, Andrew JP, Ahmed, Fayha, Nair, Devi, Whittall, Ros, Wang, Darrell, Taylor, Alison, Norbury, Gail, Humphries, Steve E·2007·European Journal of Human Genetics
DOI 10.1038/sj.ejhg.5201897
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Abstract

A novel sequence change in repeat 3 of the promoter of the low-density lipoprotein receptor (LDLR) gene, -139C>G, has been identified in a patient with familial hypercholesterolemia (FH). LDLR -139G has been passed to one offspring who also shows an FH phenotype. Transient transfection studies using luciferase gene reporter assays revealed a considerable reduction (74+/-1.4% SEM) in reporter gene expression from the -139G variant sequence compared to the wild-type sequence, strongly suggesting that this change is the basis for FH in these patients. Analysis using electrophoretic mobility shift assay demonstrated the loss of Sp1 binding to the variant sequence in vitro, explaining the reduction of transcription.

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Crossref · 10.1038/sj.ejhg.5201897

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  • Numerous mutations have been described in the LDLR promoter region that could impact SREBP-2 binding and LDLR transcriptional activation, leading to elevated cholesterol levels.

    “Numerous mutations have been described in the promotor region which could impact the ability of SREBP-2 to bind LDLR and activate transcription of the gene leading to elevated cholesterol levels35–38.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [37]

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Research works printed but not linked: 10

  1. Dedoussis GVZ, Schmidt H, Genschel J : LDL-receptor mutations in Europe. Hum Mut 2004; 24: 443–459. · DOI
  2. Miller SA, Dykes DD, Polesky HF : A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res 1988; 16: 1215. · DOI
  3. Heath KE, Humphries SE, Middleton-Price H, Boxer M : A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom. Eur J Hum Genet 2001; 9: 244–252. · DOI
  4. Bunn CF, Lintott CJ, Scott RS, George PM : Comparison of SSCP and DHPLC for the detection of LDLR mutations in a New Zealand cohort. Hum Mutat 2002; 19: 311. · DOI
  5. Dedoussis GV, Pitsavos C, Kelberman D et al: a novel mutation in the promoter (-45delT) of the low-density lipoprotein receptor gene associated with familial hypercholesterolemia. Clin Genet 2003; 64: 414–419. · DOI
  6. Sun XM, Neuwirth C, Wade DP, Knight BL, Soutar AK : 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). Hum Mol Genet 1995; 4: 2125–2129. · DOI
  7. Francova H, Trbusek M, Zapletalova P, Kuhrova V : New promoter mutations in the low-density lipoprotein receptor gene which induce familial hypercholesterolaemia phenotype: molecular and functional analysis. J Inherit Metab Dis 2004; 27: 523–528. · DOI
  8. Mozas P, Galetto R, Albajar M, Ros E, Pocovi M, Rodriguez-Rey JC : A mutation (−49C>T) in the promoter of the low density lipoprotein receptor gene associated with familial hypercholesterolemia. J Lipid Res 2002; 43: 13–18. · DOI
  9. Hobbs HH, Brown MS, Goldstein JL : Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1992; 1: 445–466. · DOI · Paper page
  10. Koivisto UM, Palvimo JJ, Janne OA, Kontula K : A single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia. Proc Natl Acad Sci USA 1994; 91: 10526–10530. · DOI

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Metadata

Authors
Smith, A. J., Ahmed, F., Nair, D., Whittall, R., Wang, D., Taylor, A., Norbury, G., & Humphries, S. E.
Venue
European Journal of Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2007-07-11
Volume
15
Issue
11
Pages
1186-1189
ISSN
  • 1018-4813
  • 1476-5438
DOI
10.1038/sj.ejhg.5201897
Cited by
25
References
0
Language
en
Licence
www.springer.com/tdm (tdm)

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