Human Molecular Genetics, Vol 8, 2025-2030, Copyright © 1999 by Oxford University Press
CL Scholtz, AV Peeters, CF Hoogendijk, R Thiart, JN Villiers, R Hillermann, J Liu, AD Marais and MJ Kotze
The low-density lipoprotein receptor (LDLR) plays a major role in
cholesterol homeostasis. Mutations in the regulatory region of the LDLR
gene, although rare, have been shown to alter transcriptional activity of
the gene and can cause familial hypercholesterolaemia (FH). In this study,
a transition (c-->t) was identified at nucleotide position -59 within
repeat 2 of the LDLR promoter in a South African FH patient of mixed
ancestry. By screening 17 family members of the index case for this
promoter mutation, two additional single base changes (-124c-->t
and-175g-->t) were identified, located at recently described cis- acting
regulatory sequences of the LDLR promoter. Both the-59c-->t and
the-124c-->t transitions were identified in the normocholesterolaemic
son of the index patient. Reporter plasmids containing the normal and
mutant promoter fragments were constructed by directional cloning.
Transcription studies using a luciferase reporter system demonstrated that
the-59c-->t mutation significantly reduces promoter activity in both the
presence and absence of sterols ( approximately 40% of normal activity),
while the-124c-->t variant increases transcription ( approximately 160%)
of the LDLR gene. The intra-familial phenotypic variability observed
amongst individuals with the-59c-->t mutation can probably be ascribed
to allelic interaction, suggesting that variation in the LDLR promoter
region may contribute sig-- nificantly to the phenotypic expression of
FH-related mutations in populations where these mutations prevail.
ARTICLES
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
MRC Cape Heart Group,
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