Open AccessA single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia.
Author(s) -
UllaMaija Koivisto,
Jorma J. Palvimo,
Olli A. Jänne,
Kimmo Kontula
Publication year - 1994
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.91.22.10526
Subject(s) - ldl receptor , internalization , microbiology and biotechnology , familial hypercholesterolemia , biology , transfection , promoter , binding site , mutation , receptor , low density lipoprotein , point mutation , gene , lipoprotein , genetics , biochemistry , cholesterol , gene expression
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.