TY - JOUR
T1 - The J. D. mutation in familial hypercholesterolemia
T2 - Amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors
AU - Davis, C. Geoffrey
AU - Lehrman, Mark A.
AU - Russell, David W.
AU - Anderson, Richard G W
AU - Brown, Michael S.
AU - Goldstein, Joseph L.
N1 - Funding Information:
We thank Edith Womack and Lavon Sanders for able assistance in growing the cultured cells. Tammy Burgess and Deborah Noble-Schles-singer provided excellent technical assistance. This research was supported by grants from the National Institutes of Health (HL 20948 and HL 31348). C. G. D. is the recipient of a postdoctoral fellowship from the National Institutes of Health (HL 06660). M. A. L. is the recipient of a fellowship from the Jane Coffin Childs Memorial Fund for Medical Research. D. W. R. is the recipient of a Research Career Development Award from the National Institutes of Health (HL 01287).
PY - 1986/4/11
Y1 - 1986/4/11
N2 - 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.
AB - 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.
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U2 - 10.1016/0092-8674(86)90533-7
DO - 10.1016/0092-8674(86)90533-7
M3 - Article
C2 - 3955657
AN - SCOPUS:0022456630
SN - 0092-8674
VL - 45
SP - 15
EP - 24
JO - Cell
JF - Cell
IS - 1
ER -