Document Detail


A single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia.
MedLine Citation:
PMID:  7937987     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have identified a Finnish family with a typical phenotype of heterozygous familial hypercholesterolemia (FH) due to a single-base substitution in the proximal Sp1 binding site of the low density lipoprotein (LDL) receptor gene promoter. The mutation, a C-->T substitution at nucleotide -43, cosegregated with the FH phenotype in six available family members and abolished binding of Sp1 transcription factor to this site. As a consequence, transcriptional activity of the mutated LDL receptor promoter was only about 1/20th of that of the wild-type promoter, as judged by transfection studies in HeLa cells. Studies of primary fibroblast cultures established from a family member revealed a markedly reduced LDL receptor mRNA concentration as well as reduction of binding, internalization, and degradation of 125I-labeled LDL to values < 50% of those in normal fibroblasts. This DNA alteration is thus a naturally occurring promoter mutation causing a severe disorder of human lipoprotein metabolism.
Authors:
U M Koivisto; J J Palvimo; O A Jänne; K Kontula
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  91     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  1994 Oct 
Date Detail:
Created Date:  1994-11-23     Completed Date:  1994-11-23     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  10526-30     Citation Subset:  IM    
Affiliation:
Institute of Biotechnology, University of Helsinki, Finland.
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MeSH Terms
Descriptor/Qualifier:
Animals
Base Sequence
Binding Sites
Cell Line
Cells, Cultured
Cercopithecus aethiops
Chloramphenicol O-Acetyltransferase / analysis,  biosynthesis
DNA / genetics,  metabolism
DNA Primers
Deoxyribonuclease I
Female
Fibroblasts / metabolism
Hela Cells
Heterozygote
Humans
Hyperlipoproteinemia Type II / genetics*,  metabolism
Male
Middle Aged
Molecular Sequence Data
Oligodeoxyribonucleotides
Pedigree
Phenotype
Point Mutation*
Polymerase Chain Reaction
Promoter Regions, Genetic*
RNA, Messenger / analysis,  biosynthesis
Receptors, LDL / biosynthesis,  genetics*
Restriction Mapping
Skin / metabolism
Sp1 Transcription Factor / metabolism*
Transfection
Chemical
Reg. No./Substance:
0/DNA Primers; 0/Oligodeoxyribonucleotides; 0/RNA, Messenger; 0/Receptors, LDL; 0/Sp1 Transcription Factor; 9007-49-2/DNA; EC 2.3.1.28/Chloramphenicol O-Acetyltransferase; EC 3.1.21.1/Deoxyribonuclease I
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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