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
. 1995 Oct 10;92(21):9905–9909. doi: 10.1073/pnas.92.21.9905

Mutant oocytic low density lipoprotein receptor gene family member causes atherosclerosis and female sterility.

H Bujo 1, T Yamamoto 1, K Hayashi 1, M Hermann 1, J Nimpf 1, W J Schneider 1
PMCID: PMC40911  PMID: 7568242

Abstract

The so-called very low density lipoprotein receptors (VLDLRs) are related to the LDLR gene family. So far, naturally occurring mutations have only been described for the prototype LDLR; in humans, they cause familial hypercholesterolemia. Here we describe a naturally occurring mutation in a VLDLR that causes a dramatic abnormal phenotype. Hens of the mutant restricted-ovulator chicken strain carry a single mutation, lack functional oocyte receptors, are sterile, and display severe hyperlipidemia with associated premature atherosclerosis. The mutation converts a cysteine residue into a serine, resulting in an unpaired cysteine and greatly reduced expression of the mutant avian VLDLR on the oocyte surface. Extraoocytic cells in the mutant produce higher than normal amounts of a differentially spliced form of the receptor that is characteristic for somatic cells but absent from germ cells.

Full text

PDF
9906

Images in this article

9906Fig. 1
on p.9906
9907Fig. 2
on p.9907
9907Fig. 3
on p.9907
9908Fig. 4
on p.9908

Selected References

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

  1. Barber D. L., Sanders E. J., Aebersold R., Schneider W. J. The receptor for yolk lipoprotein deposition in the chicken oocyte. J Biol Chem. 1991 Oct 5;266(28):18761–18770. [PubMed] [Google Scholar]
  2. Bujo H., Hermann M., Kaderli M. O., Jacobsen L., Sugawara S., Nimpf J., Yamamoto T., Schneider W. J. Chicken oocyte growth is mediated by an eight ligand binding repeat member of the LDL receptor family. EMBO J. 1994 Nov 1;13(21):5165–5175. doi: 10.1002/j.1460-2075.1994.tb06847.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Dahlbäck B., Lundwall A., Stenflo J. Primary structure of bovine vitamin K-dependent protein S. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4199–4203. doi: 10.1073/pnas.83.12.4199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Durkin M. E., Chakravarti S., Bartos B. B., Liu S. H., Friedman R. L., Chung A. E. Amino acid sequence and domain structure of entactin. Homology with epidermal growth factor precursor and low density lipoprotein receptor. J Cell Biol. 1988 Dec;107(6 Pt 2):2749–2756. doi: 10.1083/jcb.107.6.2749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gray A., Dull T. J., Ullrich A. Nucleotide sequence of epidermal growth factor cDNA predicts a 128,000-molecular weight protein precursor. Nature. 1983 Jun 23;303(5919):722–725. doi: 10.1038/303722a0. [DOI] [PubMed] [Google Scholar]
  6. Gåfvels M. E., Caird M., Britt D., Jackson C. L., Patterson D., Strauss J. F., 3rd Cloning of a cDNA encoding a putative human very low density lipoprotein/apolipoprotein E receptor and assignment of the gene to chromosome 9pter-p23. Somat Cell Mol Genet. 1993 Nov;19(6):557–569. doi: 10.1007/BF01233382. [DOI] [PubMed] [Google Scholar]
  7. Gåfvels M. E., Paavola L. G., Boyd C. O., Nolan P. M., Wittmaack F., Chawla A., Lazar M. A., Bucan M., Angelin B. O., Strauss J. F., 3rd Cloning of a complementary deoxyribonucleic acid encoding the murine homolog of the very low density lipoprotein/apolipoprotein-E receptor: expression pattern and assignment of the gene to mouse chromosome 19. Endocrinology. 1994 Jul;135(1):387–394. doi: 10.1210/endo.135.1.8013374. [DOI] [PubMed] [Google Scholar]
  8. Hayashi K., Nimpf J., Schneider W. J. Chicken oocytes and fibroblasts express different apolipoproteins-B-specific receptors. J Biol Chem. 1989 Feb 25;264(6):3131–3139. [PubMed] [Google Scholar]
  9. Ho K. J., Lawrence W. D., Lewis L. A., Liu L. B., Taylor C. B. Hereditary hyperlipidemia in nonlaying chickens. Arch Pathol. 1974 Sep;98(3):161–172. [PubMed] [Google Scholar]
  10. Hobbs H. H., Russell D. W., Brown M. S., Goldstein J. L. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet. 1990;24:133–170. doi: 10.1146/annurev.ge.24.120190.001025. [DOI] [PubMed] [Google Scholar]
  11. Jacobsen L., Hermann M., Vieira P. M., Schneider W. J., Nimpf J. The chicken oocyte receptor for lipoprotein deposition recognizes alpha 2-macroglobulin. J Biol Chem. 1995 Mar 24;270(12):6468–6475. doi: 10.1074/jbc.270.12.6468. [DOI] [PubMed] [Google Scholar]
  12. Jokinen E. V., Landschulz K. T., Wyne K. L., Ho Y. K., Frykman P. K., Hobbs H. H. Regulation of the very low density lipoprotein receptor by thyroid hormone in rat skeletal muscle. J Biol Chem. 1994 Oct 21;269(42):26411–26418. [PubMed] [Google Scholar]
  13. Kurachi K., Davie E. W. Isolation and characterization of a cDNA coding for human factor IX. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6461–6464. doi: 10.1073/pnas.79.21.6461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Leitersdorf E., Tobin E. J., Davignon J., Hobbs H. H. Common low-density lipoprotein receptor mutations in the French Canadian population. J Clin Invest. 1990 Apr;85(4):1014–1023. doi: 10.1172/JCI114531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mac Lachlan I., Nimpf J., Schneider W. J. Avian riboflavin binding protein binds to lipoprotein receptors in association with vitellogenin. J Biol Chem. 1994 Sep 30;269(39):24127–24132. [PubMed] [Google Scholar]
  16. Nimpf J., Radosavljevic M. J., Schneider W. J. Oocytes from the mutant restricted ovulator hen lack receptor for very low density lipoprotein. J Biol Chem. 1989 Jan 25;264(3):1393–1398. [PubMed] [Google Scholar]
  17. Nimpf J., Stifani S., Bilous P. T., Schneider W. J. The somatic cell-specific low density lipoprotein receptor-related protein of the chicken. Close kinship to mammalian low density lipoprotein receptor gene family members. J Biol Chem. 1994 Jan 7;269(1):212–219. [PubMed] [Google Scholar]
  18. Oka K., Ishimura-Oka K., Chu M. J., Sullivan M., Krushkal J., Li W. H., Chan L. Mouse very-low-density-lipoprotein receptor (VLDLR) cDNA cloning, tissue-specific expression and evolutionary relationship with the low-density-lipoprotein receptor. Eur J Biochem. 1994 Sep 15;224(3):975–982. doi: 10.1111/j.1432-1033.1994.00975.x. [DOI] [PubMed] [Google Scholar]
  19. Oka K., Tzung K. W., Sullivan M., Lindsay E., Baldini A., Chan L. Human very-low-density lipoprotein receptor complementary DNA and deduced amino acid sequence and localization of its gene (VLDLR) to chromosome band 9p24 by fluorescence in situ hybridization. Genomics. 1994 Mar 15;20(2):298–300. doi: 10.1006/geno.1994.1171. [DOI] [PubMed] [Google Scholar]
  20. Saito A., Pietromonaco S., Loo A. K., Farquhar M. G. Complete cloning and sequencing of rat gp330/"megalin," a distinctive member of the low density lipoprotein receptor gene family. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9725–9729. doi: 10.1073/pnas.91.21.9725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sakai J., Hoshino A., Takahashi S., Miura Y., Ishii H., Suzuki H., Kawarabayasi Y., Yamamoto T. Structure, chromosome location, and expression of the human very low density lipoprotein receptor gene. J Biol Chem. 1994 Jan 21;269(3):2173–2182. [PubMed] [Google Scholar]
  22. Schneider W. J. The low density lipoprotein receptor. Biochim Biophys Acta. 1989 May 9;988(2):303–317. doi: 10.1016/0304-4157(89)90023-3. [DOI] [PubMed] [Google Scholar]
  23. Schneider W. J. Yolk precursor transport in the laying hen. Curr Opin Lipidol. 1995 Apr;6(2):92–96. doi: 10.1097/00041433-199504000-00006. [DOI] [PubMed] [Google Scholar]
  24. Shen X., Steyrer E., Retzek H., Sanders E. J., Schneider W. J. Chicken oocyte growth: receptor-mediated yolk deposition. Cell Tissue Res. 1993 Jun;272(3):459–471. doi: 10.1007/BF00318552. [DOI] [PubMed] [Google Scholar]
  25. Stifani S., Barber D. L., Nimpf J., Schneider W. J. A single chicken oocyte plasma membrane protein mediates uptake of very low density lipoprotein and vitellogenin. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1955–1959. doi: 10.1073/pnas.87.5.1955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Takahashi S., Kawarabayasi Y., Nakai T., Sakai J., Yamamoto T. Rabbit very low density lipoprotein receptor: a low density lipoprotein receptor-like protein with distinct ligand specificity. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9252–9256. doi: 10.1073/pnas.89.19.9252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Toda T., Leszczynski D., McGibbon W. H., Kummerow F. A. Coronary arterial lesions in sexually mature non-layers, layers, and roosters. Virchows Arch A Pathol Anat Histol. 1980;388(2):123–135. doi: 10.1007/BF00430682. [DOI] [PubMed] [Google Scholar]
  28. Webb J. C., Patel D. D., Jones M. D., Knight B. L., Soutar A. K. Characterization and tissue-specific expression of the human 'very low density lipoprotein (VLDL) receptor' mRNA. Hum Mol Genet. 1994 Apr;3(4):531–537. doi: 10.1093/hmg/3.4.531. [DOI] [PubMed] [Google Scholar]
  29. Wen D. Z., Dittman W. A., Ye R. D., Deaven L. L., Majerus P. W., Sadler J. E. Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene. Biochemistry. 1987 Jul 14;26(14):4350–4357. doi: 10.1021/bi00388a025. [DOI] [PubMed] [Google Scholar]
  30. 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