Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1995-06-07
2001-05-29
Kunz, Gary L. (Department: 1647)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S04400A, C536S024100
Reexamination Certificate
active
06239270
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a cDNA clone encoding a human calcium sensor protein of parathyroid, placental, and kidney tubule cells.
In WO 88/03271 there is described monoclonal antiparathyroid antibodies identifying a parathyroid cell membrane-bound calcium receptor or sensor, crucially involved in calcium regulation of the parathyroid hormone (PTH) release (1,2). The receptor function is essential for maintenance of normal plasma calcium concentrations, and reduced receptor expression within proliferating parathyroid cells of patients with hyperparathyroidism (HPT) results in calcium insensitivity of the PTH secretion and variably severe hypercalcemia (3-6). Reactivity with the antiparathyroid antibodies was also demonstrated for proximal kidney tubule cells and cytotrophoblast cells of the human placenta, and the cytotrophoblasts were demonstrated to exhibit an almost parathyroid-identical regulation of cytoplasmic calcium [Ca
2+
i](7,8). The antibody-reactive structure was found to exert calcium sensing function also in the cytotrophoblasts, and as these cells constitute part of the syncytium, the calcium sensor was suggested to be actively involved in the calcium homeostasis of the fetus (7,8). It was proposed that the antibody-reactive structure of the proximal kidney tubule cells exerts a similar calcium sensing function, and that the calcium sensor, thus, plays a more universal role in calcium regulation via different organ systems (1,7,9,10).
On HPT patients with hypercalcemia, surgery is-performed to remove one or more of the parathyroid glands. It would be greatly desirable to have alternatives to this surgical procedure as HPT has proven to be a very common disorder and surgery is a relatively costly procedure and sometimes even entails some risks for the patients.
The calcium sensor/receptor has been revealed as a 500 kDa single chain glycoprotein (7). However, the amino acid sequence as well as the corresponding DNA sequences thereof are hitherto unknown.
SUMMARY OF THE INVENTION
Therefore, an object of the present invention was to provide sufficient structural data of the calcium sensor/receptor to enable complete characterization thereof.
In one embodiment, the present invention provides the complete amino acid sequence of the human calcium sensor protein and nucleic acid probes for identifying other novel calcium sensor proteins.
Another object is to use said structural data to design novel treatment methods as well as compounds and compositions for treating calcium related disorders.
In other embodiments, the present invention provides identification of peptide regions within the calcium sensor protein cytoplasmic domain which are homologous to SH2 and SH3 binding motifs involved in signal transduction pathways.
Two important human diseases associated with perturbations of the calcium ion homeostasis are hyperthyroidism and osteoporosis. Thus, in one embodiment cells expressing the calcium sensor protein or a fragment thereof or comprising the cDNA encoding the calcium sensor protein of the present invention may be utilized in an assay to identify molecules which block or enhance the activity of the calcium sensor protein, including signal transduction pathways associated with the activity of the sensor. These molecules will be useful in the treatment of mammalian pathological conditions associated with perturbations in the levels of PTH, vitamins D3 production, estrogen, osteoclast activity or osteoblast activity (therefore, bone resorption and/or formation), calcium secretion and calcium ion homeostasis.
The present invention describes the isolation and characterization of cDNA clones encoding the calcium sensor/receptor in human placenta and Northern blots verifying the presence of the corresponding mRNA within the parathyroid and kidney. Close sequence similarity between the calcium sensor and a rat Heymann nephritis antigen, gp330 (11, 67), suggests that the common calcium sensor of the placenta, the parathyroid and kidney tubule is related to this antigen, represents the human homologue of gp330, and belongs to a family of large glycoproteins with receptor function and calcium binding ability. Therefore, a further object of this invention is to provide diagnostic assays and therapeutic methods based on human gp330.
REFERENCES:
Godson et al.,JBC, vol. 268, pp. 11946-11950, Jun. 5, 1993.
C. Juhlin et al., “500-Kilodalton calcium sensor regulating cytoplasmic Ca2+ in cytotrophoblast cells of human placenta,”J. Biol. Chem., 265(14) pp. 8275-8279, 1990.
A. Saito et al., “Complete cloning and sequencing if rat gp330/“megalin,” a distinctive member of the low density lipoprotein receptor gene family,”Proc. Nat'l. Acad. Sci. U.S.A., 91(21) pp. 9725-9729, 1994.
R. Raychowdhury et al., “Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor,”Science, 244(4909), pp. 1163-1165, 1989.
C. Juhlin et al., “Monoclonal antibodies with exclusive reactivity against paratheyroid cells and tubule cells of the kidney,”Proc. Nat'l. Acad. Sci. U.S.A., 84(9), pp. 2990-2994, 1987.
S. Lundgren et al., “A protein involved in calcium sensing of the human parathyroid and placental cytotrophoblast cells belongs to the LDL-receptor protein superfamily,”Exp. Cell Res., 212(2), PP. 344-350, 1994.
E.M. Brown et al., “Molecular mechanisms underlying the sensing of extracellular Ca2+ by parathyroid and kidney cells,”Eur. J. Endocrinol. 132 (5), pp. 523-31, 1995.
S.K. Moestrup, “The alpha 2-macroglobulin recepto and epithelial glycopotein-330; two giant receptors mediating endocytosis of multiple ligands,”Biochim. Biophys. Acta., 1197(2), pp. 197-213, 1994.
M.G. Farquhar et al., “gp330 and RAP: the Heymann nephritis antigenic complex,”Ann. N. Y. Acad. Sci., 737, pp. 96-113, 1994.
M.S. Kounnas et al., “An overview of the structure and function of glycoprotein 330, a receptor related to the alph 2-macroglobulin receptor,”Ann. N.Y. Acad. Sci., 737 pp. 114-123, 1994.
S.K. Moestrup et al., “Binding and endocytosis of proteins mediated by epithelial gp330,”Ann N Y Acad. Sci., 737, pp. 124-137, 1994.
Akerstrom Goran
Crumley Gregg R.
Hjälm Göran
Juhlin Claes
Morse Clarence C.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Gucker Stephen
Kunz Gary L.
Rhone-Poulenc Rorer S.A.
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