Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1986 Jun;83(11):3679–3683. doi: 10.1073/pnas.83.11.3679

Exon-Alu recombination deletes 5 kilobases from the low density lipoprotein receptor gene, producing a null phenotype in familial hypercholesterolemia.

M A Lehrman, D W Russell, J L Goldstein, M S Brown
PMCID: PMC323586  PMID: 3012527

Abstract

Among patients with familial hypercholesterolemia, half of the mutant alleles at the low density lipoprotein (LDL) receptor locus produce no immunologically detectable protein. To determine the molecular basis for one such null allele, we have cloned an abnormally short restriction fragment from the genomic DNA of one patient. The DNA sequence revealed a 5-kilobase deletion that joins a coding sequence in exon 13 to an Alu repetitive element in intron 15. The deletion joint is flanked by two inverted repeats that could potentially form a double stem-loop structure that might have predisposed to this deletion. A similar double stem-loop structure can be drawn for a previously described deletion in the LDL receptor gene and for a deletion in the beta-globin gene cluster. We speculate that such double stem-loop structures might contribute to the formation of large deletions in the human genome.

Full text

PDF
3683

Images in this article

3680Image
on p.3680
3681Image
on p.3681
3682Image
on p.3682

Selected References

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

  1. Beisiegel U., Schneider W. J., Brown M. S., Goldstein J. L. Immunoblot analysis of low density lipoprotein receptors in fibroblasts from subjects with familial hypercholesterolemia. J Biol Chem. 1982 Nov 10;257(21):13150–13156. [PubMed] [Google Scholar]
  2. Brown M. S., Goldstein J. L. Analysis of a mutant strain of human fibroblasts with a defect in the internalization of receptor-bound low density lipoprotein. Cell. 1976 Dec;9(4 Pt 2):663–674. doi: 10.1016/0092-8674(76)90130-6. [DOI] [PubMed] [Google Scholar]
  3. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Davis C. G., Lehrman M. A., Russell D. W., Anderson R. G., Brown M. S., Goldstein J. L. The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors. Cell. 1986 Apr 11;45(1):15–24. doi: 10.1016/0092-8674(86)90533-7. [DOI] [PubMed] [Google Scholar]
  5. Deininger P. L., Jolly D. J., Rubin C. M., Friedmann T., Schmid C. W. Base sequence studies of 300 nucleotide renatured repeated human DNA clones. J Mol Biol. 1981 Sep 5;151(1):17–33. doi: 10.1016/0022-2836(81)90219-9. [DOI] [PubMed] [Google Scholar]
  6. Goldstein J. L., Brown M. S., Anderson R. G., Russell D. W., Schneider W. J. Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. Annu Rev Cell Biol. 1985;1:1–39. doi: 10.1146/annurev.cb.01.110185.000245. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Harding J. D., MacDonald R. J., Przybyla A. E., Chirgwin J. M., Pictet R. L., Rutter W. J. Changes in the frequency of specific transcripts during development of the pancreas. J Biol Chem. 1977 Oct 25;252(20):7391–7397. [PubMed] [Google Scholar]
  9. Hobbs H. H., Lehrman M. A., Yamamoto T., Russell D. W. Polymorphism and evolution of Alu sequences in the human low density lipoprotein receptor gene. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7651–7655. doi: 10.1073/pnas.82.22.7651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Horsthemke B., Kessling A. M., Seed M., Wynn V., Williamson R., Humphries S. E. Identification of a deletion in the low density lipoprotein (LDL) receptor gene in a patient with familial hypercholesterolaemia. Hum Genet. 1985;71(1):75–78. doi: 10.1007/BF00295672. [DOI] [PubMed] [Google Scholar]
  11. Jagadeeswaran P., Tuan D., Forget B. G., Weissman S. M. A gene deletion ending at the midpoint of a repetitive DNA sequence in one form of hereditary persistence of fetal haemoglobin. Nature. 1982 Apr 1;296(5856):469–470. doi: 10.1038/296469a0. [DOI] [PubMed] [Google Scholar]
  12. Lehrman M. A., Goldstein J. L., Brown M. S., Russell D. W., Schneider W. J. Internalization-defective LDL receptors produced by genes with nonsense and frameshift mutations that truncate the cytoplasmic domain. Cell. 1985 Jul;41(3):735–743. doi: 10.1016/s0092-8674(85)80054-4. [DOI] [PubMed] [Google Scholar]
  13. Lehrman M. A., Schneider W. J., Südhof T. C., Brown M. S., Goldstein J. L., Russell D. W. Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science. 1985 Jan 11;227(4683):140–146. doi: 10.1126/science.3155573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Loenen W. A., Blattner F. R. Lambda Charon vectors (Ch32, 33, 34 and 35) adapted for DNA cloning in recombination-deficient hosts. Gene. 1983 Dec;26(2-3):171–179. doi: 10.1016/0378-1119(83)90187-7. [DOI] [PubMed] [Google Scholar]
  15. Orkin S. H., Kazazian H. H., Jr The mutation and polymorphism of the human beta-globin gene and its surrounding DNA. Annu Rev Genet. 1984;18:131–171. doi: 10.1146/annurev.ge.18.120184.001023. [DOI] [PubMed] [Google Scholar]
  16. Ottolenghi S., Giglioni B. The deletion in a type of delta 0-beta 0-thalassaemia begins in an inverted AluI repeat. Nature. 1982 Dec 23;300(5894):770–771. doi: 10.1038/300770a0. [DOI] [PubMed] [Google Scholar]
  17. Russell D. W., Yamamoto T., Schneider W. J., Slaughter C. J., Brown M. S., Goldstein J. L. cDNA cloning of the bovine low density lipoprotein receptor: feedback regulation of a receptor mRNA. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7501–7505. doi: 10.1073/pnas.80.24.7501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Schmid C. W., Jelinek W. R. The Alu family of dispersed repetitive sequences. Science. 1982 Jun 4;216(4550):1065–1070. doi: 10.1126/science.6281889. [DOI] [PubMed] [Google Scholar]
  20. Südhof T. C., Goldstein J. L., Brown M. S., Russell D. W. The LDL receptor gene: a mosaic of exons shared with different proteins. Science. 1985 May 17;228(4701):815–822. doi: 10.1126/science.2988123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Vanin E. F., Henthorn P. S., Kioussis D., Grosveld F., Smithies O. Unexpected relationships between four large deletions in the human beta-globin gene cluster. Cell. 1983 Dec;35(3 Pt 2):701–709. doi: 10.1016/0092-8674(83)90103-4. [DOI] [PubMed] [Google Scholar]
  22. Yamamoto T., Davis C. G., Brown M. S., Schneider W. J., Casey M. L., Goldstein J. L., Russell D. W. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984 Nov;39(1):27–38. doi: 10.1016/0092-8674(84)90188-0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES