Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1978 Mar;61(3):678–696. doi: 10.1172/JCI108980

Genetics of the low density lipoprotein receptor. Diminished receptor activity in lymphocytes from heterozygotes with familial hypercholesterolemia.

D W Bilheimer, Y K Ho, M S Brown, R G Anderson, J L Goldstein
PMCID: PMC372581  PMID: 205553

Abstract

Using circulating mononuclear cells as a readily available tissue and using the rate of high affinity degradation of 125-I-labeled low density lipoprotein (LDL) as an index of cell surface LDL receptor activity, we have measured receptor activity in cells from 53 individuals. This group includes 32 healthy subjects, 15 subjects with the heterozygous form of familial hypercholesterolemia, and 6 subjects with hyperlipidemic disorders other than familial hypercholesterolemia. 7 of the healthy subjects and 10 of the heterozygotes were members of a single large kindred with five-generation transmission of the mutant familial hypercholesterolemia gene. LDL receptor activity was assayed in blood mononuclear cells under two sets of conditions. First, 125I-LDL degradation was measured in purified lymphocytes that had been incubated for 3 days in the absence of lipoproteins so as to induce a high level of LDL receptor activity. Phase-contrast autoradiograms of cells incubated with 125I-LDL and electron micrographs of cells incubated with ferritin-labeled LDL confirmed the existence of LDL receptors on lymphocytes. Second, 125I-LDL degradation was measured in mixed mononuclear cells (85-90% lymphocytes and 5-15% monocytes) immediately after their isolation from the bloodstream. This assay represented an attempt to assess the number of receptors actually expressed on the cells when they were in the circulation. Under both sets of conditions, cells from the familial hypercholesterolemia heterozygotes expressed an average of about one-half the normal number of LDL receptors. The current findings are consistent with the conclusion that heterozygotes with familial hypercholesterolemia possess only one functional allele at the LDL receptor locus and that the consequent deficiency of LDL receptors produces the clinical syndrome of heterozygous familial hypercholesterolemia.

Full text

PDF
678

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson R. G., Brown M. S., Goldstein J. L. Role of the coated endocytic vesicle in the uptake of receptor-bound low density lipoprotein in human fibroblasts. Cell. 1977 Mar;10(3):351–364. doi: 10.1016/0092-8674(77)90022-8. [DOI] [PubMed] [Google Scholar]
  2. Anderson R. G., Goldstein J. L., Brown M. S. Localization of low density lipoprotein receptors on plasma membrane of normal human fibroblasts and their absence in cells from a familial hypercholesterolemia homozygote. Proc Natl Acad Sci U S A. 1976 Jul;73(7):2434–2438. doi: 10.1073/pnas.73.7.2434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown M. S., Dana S. E., Goldstein J. L. Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured human fibroblasts. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. J Biol Chem. 1974 Feb 10;249(3):789–796. [PubMed] [Google Scholar]
  4. Brown M. S., Goldstein J. L. Familial hypercholesterolemia: A genetic defect in the low-density lipoprotein receptor. N Engl J Med. 1976 Jun 17;294(25):1386–1390. doi: 10.1056/NEJM197606172942509. [DOI] [PubMed] [Google Scholar]
  5. Brown M. S., Goldstein J. L. Receptor-mediated control of cholesterol metabolism. Science. 1976 Jan 16;191(4223):150–154. doi: 10.1126/science.174194. [DOI] [PubMed] [Google Scholar]
  6. Brown M. S., Goldstein J. L. Regulation of the activity of the low density lipoprotein receptor in human fibroblasts. Cell. 1975 Nov;6(3):307–316. doi: 10.1016/0092-8674(75)90182-8. [DOI] [PubMed] [Google Scholar]
  7. Goldstein J. L., Brown M. S. Binding and degradation of low density lipoproteins by cultured human fibroblasts. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. J Biol Chem. 1974 Aug 25;249(16):5153–5162. [PubMed] [Google Scholar]
  8. Goldstein J. L., Brown M. S. Expression of the familial hypercholesterolemia gene in heterozygotes: model for a dominant disorder in man. Trans Assoc Am Physicians. 1974;87:120–131. [PubMed] [Google Scholar]
  9. Goldstein J. L., Brown M. S., Stone N. J. Genetics of the LDL receptor: evidence that the mutations affecting binding and internalization are allelic. Cell. 1977 Nov;12(3):629–641. doi: 10.1016/0092-8674(77)90263-x. [DOI] [PubMed] [Google Scholar]
  10. Goldstein J. L., Brown M. S. The low-density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem. 1977;46:897–930. doi: 10.1146/annurev.bi.46.070177.004341. [DOI] [PubMed] [Google Scholar]
  11. Goldstein J. L., Schrott H. G., Hazzard W. R., Bierman E. L., Motulsky A. G. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest. 1973 Jul;52(7):1544–1568. doi: 10.1172/JCI107332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Goldstein J. L., Sobhani M. K., Faust J. R., Brown M. S. Heterozygous familial hypercholesterolemia: failure of normal allele to compensate for mutant allele at a regulated genetic locus. Cell. 1976 Oct;9(2):195–203. doi: 10.1016/0092-8674(76)90110-0. [DOI] [PubMed] [Google Scholar]
  13. Ho Y. K., Brown S., Bilheimer D. W., Goldstein J. L. Regulation of low density lipoprotein receptor activity in freshly isolated human lymphocytes. J Clin Invest. 1976 Dec;58(6):1465–1474. doi: 10.1172/JCI108603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ho Y. K., Faust J. R., Bilheimer D. W., Brown M. S., Goldstein J. L. Regulation of cholesterol synthesis by low density lipoprotein in isolated human lymphocytes. Comparison of cells from normal subjects and patients with homozygous familial hypercholesterolemia and abetalipoproteinemia. J Exp Med. 1977 Jun 1;145(6):1531–1549. doi: 10.1084/jem.145.6.1531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  16. Langer T., Strober W., Levy R. I. The metabolism of low density lipoprotein in familial type II hyperlipoproteinemia. J Clin Invest. 1972 Jun;51(6):1528–1536. doi: 10.1172/JCI106949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Schrott H. G., Goldstein J. L., Hazzard W. R., McGoodwin M. M., Motulsky A. G. Familial hypercholesterolemia in a large indred. Evidence for a monogenic mechanism. Ann Intern Med. 1972 May;76(5):711–720. doi: 10.7326/0003-4819-76-5-711. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES