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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
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
Brown, E.M. et al. Cloning, expression, and characterization of an extracellular Ca2+ sensing receptor from bovine parathyroid. Nature 366, 575–580 (1993).
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).
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).
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).
Pollak, M.R. et al. Autosomal dominant hypocalcaemia caused by a Ca2+-sensing receptor gene mutation. Nature Genet. 8, 303–307 (1994).
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).
Law, W. & Heath, H. Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families. Ann. intern. Med. 102, 511–519 (1985).
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).
Marx, S.J., Fraser, D. & Rapoport, A. Familial hypocalciuric hypercalcemia. Am. J. Med. 78, 15–22 (1985).
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).
Blair, J.W. & Carachi, R. Neonatal primary hyperparathyroidism — a case report and review of the literature. Eur. J. Pediatr. Surg. 1, 110–114 (1991).
Hendrickson, B.A. et al. Altered hepatic transport of IgA in mice lacking J chain. J. exp. Med. (in the press).
Dunn, T.B. Melanoblasts in the stroma of the parathyroid glands of strain C58 mice. J. natn. Cancer Inst. 10, 725–733 (1949).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Ingman, F. & Ringbom, A. Spectrophotometric determination of small amounts of magnesium, and calcium employing calmagite. Microchem J. 10, 545–553 (1966).
Author information
Authors and Affiliations
Rights 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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng1295-389
This article is cited by
-
A novel mouse model for familial hypocalciuric hypercalcemia (FHH1) reveals PTH-dependent and independent CaSR defects
Pflügers Archiv - European Journal of Physiology (2024)
-
Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways
Nature Communications (2023)
-
Cellular and molecular mechanisms of the organogenesis and development, and function of the mammalian parathyroid gland
Cell and Tissue Research (2023)
-
Implications of regulator of G-protein signaling 5 expression in the pathogenesis of primary and secondary hyperparathyroidism
BMC Endocrine Disorders (2022)
-
Genotype–Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism
Calcified Tissue International (2022)