Genetics of the LDL receptor: Evidence that the mutations affecting binding and internalization are allelic

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Study of the binding, internalization, and degradation of 125l-labeled low density lipoprotein (LDL) in human fibroblasts has disclosed a new mutant allele at the LDL receptor locus. This mutant allele, designated Rb+,io, specifies a receptor molecule that is able to bind 125l-LDL but is unable to facilitate the internalization of the receptor-bound lipoprotein. This allele has been identified through analysis of fibroblasts from four heterozygous relatives of patient J.D., the previously described subject with the clinical syndrome of homozygous familial hypercholesterolemia whose fibroblasts bind but do not internalize 125l-LDL (Brown and Goldstein, 1976c). The current pedigree data reveal that J.D. is a genetic compound. From his father, he has inherited the Rb+,io allele. From his mother, J.D. has inherited the Rbo allele, a previously characterized mutant allele that specifies a receptor that is unable to bind LDL and hence is biochemically silent in J.D. Thus the only detectable receptors in the J.D. cells are the products of the Rb+,io allele that can bind, but not internalize, 125l-LDL. The demonstration that the LDL-binding and internalization defects do not complement one another in J.D. supports the conclusion that the mutations causing these two defects are allelic. This in turn suggests that the LDL receptor contains two functional sites on the same polypeptide chain-one that binds LDL and one that is necessary to mediate the internalization of the receptorbound lipoprotein.

Original languageEnglish (US)
Pages (from-to)629-641
Number of pages13
Issue number3
StatePublished - Nov 1977

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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