Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism

Abstract

Mice lacking the calcium–sensing receptor (Casr) were created to examine the receptor's role in calcium homeostasis and to elucidate the mechanism by which inherited human Casr gene defects cause diseases. Casr+/− mice, analogous to humans with familial hypocalciuric hypercalcemia, had benign and modest elevations of serum calcium, magnesium and parathyroid hormone levels as well as hypocalciuria. In contrast, Casr−/− mice, like humans with neonatal severe hyperparathyroidism, had markedly elevated serum calcium and parathyroid hormone levels, parathyroid hyperplasia, bone abnormalities, retarded growth and premature death. Our findings suggest that Casr mutations cause these human disorders by reducing the number of functional receptor molecules on the cell surface.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Brown, E.M. et al. Cloning, expression, and characterization of an extracellular Ca2+ sensing receptor from bovine parathyroid. Nature 366, 575–580 (1993).

    Article  CAS  Google Scholar 

  2. Riccardi, D. et al. Cloning and functional expression of a rat kidney extracellular calcium-sensing receptor. Proc. natn. Acad. Sci. U.S.A. 92, 131–135 (1994).

    Article  Google Scholar 

  3. Ruat, M., Molliver, M.E., Snowman, A.M. & Snyder, S.H. Calcium sensing receptor molecular cloning in rat and localization to nerve terminals. Proc. natn. Acad. Sci. U.S.A. 92, 3161–3165 (1995).

    Article  CAS  Google Scholar 

  4. Pollak, M.R. et al. Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75, 1297–1303 (1993).

    Article  CAS  Google Scholar 

  5. Pollak, M.R. et al. Autosomal dominant hypocalcaemia caused by a Ca2+-sensing receptor gene mutation. Nature Genet. 8, 303–307 (1994).

    Article  CAS  Google Scholar 

  6. Marx, S.J. et al. The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds. Medicine Baltimore 60, 397–412 (1981).

    Article  CAS  Google Scholar 

  7. Law, W. & Heath, H. Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families. Ann. intern. Med. 102, 511–519 (1985).

    Article  Google Scholar 

  8. McMurtry, C.T. et al. Significant developmental elevation in serum parathyroid hormone levels in a large kindred with familial benign (hypocalciuric) hypercalcemia. Am. J. Med. 93, 247–258 (1992).

    Article  CAS  Google Scholar 

  9. Marx, S.J., Fraser, D. & Rapoport, A. Familial hypocalciuric hypercalcemia. Am. J. Med. 78, 15–22 (1985).

    Article  CAS  Google Scholar 

  10. Pollak, M.R. et al. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism: The effects of mutant gene dosage on phenotype. J. clin. Invest. 93, 1108–1112 (1994).

    Article  CAS  Google Scholar 

  11. Blair, J.W. & Carachi, R. Neonatal primary hyperparathyroidism — a case report and review of the literature. Eur. J. Pediatr. Surg. 1, 110–114 (1991).

    Article  CAS  Google Scholar 

  12. Hendrickson, B.A. et al. Altered hepatic transport of IgA in mice lacking J chain. J. exp. Med. (in the press).

  13. Dunn, T.B. Melanoblasts in the stroma of the parathyroid glands of strain C58 mice. J. natn. Cancer Inst. 10, 725–733 (1949).

    CAS  Google Scholar 

  14. Hummel, K.P., Richardson, F.L. & Fekete, E. Anatomy. In Biology of the laboratory mouse. (ed. Green, E.L.) 258–259 (The Blakiston Division, McGraw-Hill Book Company, New York, 1966).

    Google Scholar 

  15. Marx, S.J. et al. An association between neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia in three kindreds. New Engl. J. Med. 306, 257–264 (1982).

    Article  CAS  Google Scholar 

  16. Powell, B.R., Blank, E., Benda, G. & Buist, N.R.M. Neonatal hyperparathyroidism and skeletal demineralization in an infant with familial hypocalciuric hypercalcemia. Pediatrics 91, 144–145 (1992).

    Google Scholar 

  17. Brown, E.M., Extracellular Ca2+ sensing, regulation of parathyroid cell function, and role of Ca2+ and other ions as extracellular (first) messengers. Physiol. Rev. 71, 371–411 (1991).

    Article  CAS  Google Scholar 

  18. Brent, G.A., LeBoff, M.S., Seely, E.W., Conlin, P.R. & Brown, E.M. Relationship between the concentration and rate of change of calcium and serum intact parathyroid hormone levels in normal humans. J. clin. endocrinol. Metab. 67, 944–950 (1988).

    Article  CAS  Google Scholar 

  19. Brown, E.M., Pollak, M. & Hebert, S.C. Sensing of Extracellular Ca2+ by parathyroid and kidney cells: cloning and characterization of an extracellular Ca2+-sensing receptor. Am. J. Kid. Dis. 25, 506–513 (1995).

    Article  CAS  Google Scholar 

  20. Warren, H.B., Lausen, N.C.C., Segre, G.V., EI-Hajj, G. & Brown, E.M. Regulation of calciotropic hormones in vivo in the New Zealand white rabbit. Endocrinology 125, 2683–2690 (1989).

    Article  CAS  Google Scholar 

  21. Bradley, A. Production and analysis of chimeric mice. In Terotocardnomas and Embryonic Stem Cells: A Practical Approach. (ed. Robertson, E.J.) 113–151 (IRL Press, Oxford, 1987).

    Google Scholar 

  22. Erickson, P.A., Lewis, G.R. & Fisher, S.K. Postembedding immunocytochemical techniques for light and electron microscopy. In Antibodies in cell biology. (ed. Asai, DJ.) 283–310 (Academic Press, Inc., San Diego, 1993).

    Google Scholar 

  23. Sarkar, B.C.R. & Chauhan, U.R. A new method for determining micro quantities of calcium in biological materials. Analyt. Biochem. 20, 155–166 (1967).

    Article  CAS  Google Scholar 

  24. Ingman, F. & Ringbom, A. Spectrophotometric determination of small amounts of magnesium, and calcium employing calmagite. Microchem J. 10, 545–553 (1966).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ho, C., Conner, D., Pollak, M. et al. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 11, 389–394 (1995). https://doi.org/10.1038/ng1295-389

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1295-389

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing