Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit.
The Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal with familial hypercholesterolemia, produces a mutant receptor for plasma low-density lipoprotein (LDL) that is not transported to the cell surface at a normal rate. Cloning and sequencing of complementary DNA's from normal and WHHL rabbits, shows that this defect arises from an in-frame deletion of 12 nucleotides that eliminates four amino acids from the cysteine-rich ligand binding domain of the LDL receptor. A similar mutation, detected by S1 nuclease mapping of LDL receptor messenger RNA, occurred in a patient with familial hypercholesterolemia whose receptor also fails to be transported to the cell surface. These findings suggest that animal cells may have fail-safe mechanisms that prevent the surface expression of improperly folded proteins with unpaired or improperly bonded cysteine residues.
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D002872:Chromosome Deletion; D003001:Cloning, Molecular; D003545:Cysteine / Q000235:genetics; D004247:DNA; D004262:DNA Restriction Enzymes; D005796:Genes; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D009154:Mutation; D012333:RNA, Messenger; D011817:Rabbits; D011973:Receptors, LDL / Q000235:genetics*
D012333:RNA, Messenger; D011973:Receptors, LDL; D004247:DNA; D004262:DNA Restriction Enzymes; D003545:Cysteine