A SINGLE-BASE SUBSTITUTION IN THE PROXIMAL SP1 SITE OF THE HUMAN LOW-DENSITY-LIPOPROTEIN RECEPTOR PROMOTER AS A CAUSE OF HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

We have identified a Finnish family with a typical phenotype of heterozygous familial hypercholesterolemia (FH) due to a single-base substitution in the proximal Spl 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 Spl 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 I-125-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.