Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain.

Certain mutant alleles at the low density lipoprotein (LDL) receptor locus produce receptors that bind LDL normally, but fail to cluster in coated pits and therefore cannot transport LDL into cells. We prepared genomic DNA libraries from cells of two individuals with this phenotype (internalization-defective familial hypercholesterolemia) and isolated the segment of the gene encoding the COOH-terminal cytoplasmic domain of the receptor. One mutant gene contains a single base substitution that changes a tryptophan codon (TGG) to a termination codon (TGA). This produces a receptor with only two amino acids in the cytoplasmic domain. The second mutant gene contains a four-base duplication, producing a frameshift that alters the reading frame. The cytoplasmic tail of this receptor has six of the normal amino acids plus eight additional amino acids. These data suggest that the signal for targeting the LDL receptor to coated pits resides in the cytoplasmic domain of the molecule.