title: A single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia.
abstract: 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.affiliation: Institute of Biotechnology, University of Helsinki, Finland.
authors.forename: U M
authors.initials: UM
authors.lastname: Koivisto
authors.forename: J J
authors.initials: JJ
authors.lastname: Palvimo
authors.forename: O A
authors.initials: OA
authors.lastname: Jänne
authors.forename: K
authors.initials: K
authors.lastname: Kontula
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000032:analysis / Q000096:biosynthesis; D002522:Chlorocebus aethiops; D004247:DNA / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers; D003850:Deoxyribonuclease I; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006367:HeLa Cells; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D011973:Receptors, LDL / Q000096:biosynthesis / Q000235:genetics*; D015183:Restriction Mapping; D012867:Skin / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014162:Transfection
chemical_list: D017931:DNA Primers; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D011973:Receptors, LDL; D016329:Sp1 Transcription Factor; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase; D003850:Deoxyribonuclease I