The J. D. mutation in familial hypercholesterolemia: Amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors

C. Geoffrey Davis, Mark A. Lehrman, David W. Russell, Richard G W Anderson, Michael S. Brown, Joseph L. Goldstein

Research output: Contribution to journalArticle

228 Scopus citations

Abstract

Genomic DNA encompassing the terminal exons of the gene for the low density lipoprotein (LDL) receptor was isolated from J. D., a patient with familial hypercholesterolemia whose receptor fails to cluster in coated pits. The DNA sequence revealed a substitution of a cysteine codon for a tyrosine codon at residue 807 in the cytoplasmic domain of the receptor. We reproduced this substitution through oligonucleotide-directed mutagenesis of the normal human receptor cDNA. Upon transfection into receptor-deficient hamster cells, the cDNA specified a receptor that bound LDL normally, but entered the cell slowly. Electron microscopy showed that this receptor was distributed diffusely over the cell surface, whereas the receptor produced by the normal cDNA was concentrated in coated pits. These results support the hypothesis that cytoplasmic domains direct receptors to coated pits, thereby determining the high rate of receptor internalization in animal cells.

Original languageEnglish (US)
Pages (from-to)15-24
Number of pages10
JournalCell
Volume45
Issue number1
DOIs
StatePublished - Apr 11 1986

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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