Abstract
Normal mineral metabolism and skeletal development depend on an intricate interplay of parathyroid, renal, and skeletal factors. Crucial in this respect is parathyroid hormone (PTH), which is synthesized and secreted from the parathyroid glands and at a rate inversely proportional to the serum-ionized calcium concentration. Hormone secretion is tightly regulated through the interaction of extracellular calcium with specific calciumsensing receptors (CaSRs) (1–3) that are present on the surface of the parathyroid cell. In turn, PTH regulates mineral metabolism and skeletal homeostasis through its actions on specialized target cells in bone and kidney that express the PTH/parathyroid hormonerelated peptide (PTHrP) or type 1 PTH receptor. The integrated actions of PTH and 1,25–dihydroxyvitamin D on these target tissues provide a precise system of control and maintain the serum-ionized calcium concentration within a narrow range that is critical for many physiological processes.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Hebert SC, Brown EM. The extracellular calcium receptor. [Review] [64 refs]. Curr Opin Cell Biol 1995;7:484–492.
Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature 1993;366:575–580.
Chattopadhyay N, Mithal A, Brown EM. The calcium-sensing receptor: a window into the physiology and pathophysiology of mineral ion metabolism. Endocr Rev 1996;17:289–307.
Ahn TG, Antonarakis SE, Kronenberg HM, Igarashi T, Levine MA. Familial isolated hypoparathyroidism: a molecular genetic analysis of 8 families with 23 affected persons. Medicine 1986;65:73–81.
Neer EJ. Heterotrimeric G Proteins: organizers of transmembrane signals. Cell 1995;80:249–257.
Gudermann T, Nurnberg B, Schultz G. Receptors and G proteins as primary components of transmembrane signal transduction. Part 1. G-protein-coupled receptors: structure and function. J Mol Med 1995; 73:51–63.
Nurnberg B, Gudermann T, Schultz G. Receptors and G proteins as primary components of transmembrane signal transduction. Part 2. G proteins: structure and function. J Mol Med 1995;73:123–132.
Yamaguchi T, Chattopadhyay N, Brown EM. G protein-coupled extracellular Ca2+ (Ca2+o)-sensing receptor (CaR): roles in cell signaling and control of diverse cellular functions. Adv Pharmacol 2000; 47:209–53.:209–253.
Schipani E, Karga H, Karaplis AC, et al. Identical complementary deoxyribonucleic acids encode a human renal and bone parathyroid hormone (PTH)/PTH-related peptide receptor. Endocrinology 1993; 132:2157–2165.
Abou Samra AB, Juppner H, Force T, et al. Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci USA 1992;89:2732–2736.
Juppner H, Abou Samra AB, Freeman M, et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 1991;254:1024–1026.
Adams AE, Pines M, Nakamoto C, et al. Probing the bimolecular interaction of parathyroid hormone (PTH) and the human PTH/PTHrP receptor. II. Cloning, characterization of, and photoaffinity crosslinking to the recombinant human PTH/PTHrP receptor. Biochemistry 1995;34:10,553–10,559.
Behar V, Pines M, Nakamoto C, et al. The human PTH2 receptor: binding and signal transduction properties of the stably expressed recombinant receptor. Endocrinology 1996;137:2748–2757.
Usdin TB, Gruber C, Bonner TI. Identification and functional expression of a receptor selectively recognizing parathyroid hormone, the PTH2. J Biol Chem 1995;270:15,455–15,458.
Usdin TB. Evidence for a parathyroid hormone-2 receptor selective ligand in the hypothalamus. Endocrinology 1997;138:831–834.
Hoare SR, Clark JA, Usdin TB. Molecular determinants of tuberoinfundibular peptide of 39 residues (TIP39) selectivity for the parathyroid hormone-2 (PTH2) receptor. N-terminal truncation of TIP39 reverses PTH2 receptor/PTH1 receptor binding selectivity. J Biol Chem 2000;275:27,274–27,283.
Schwindinger WF, Fredericks J, Watkins L, et al. Coupling of the PTH/PTHrP receptor to multiple G-proteins. Direct demonstration of receptor activation of Gs, Gq/11, and Gi(1) by [alpha- 32P]GTPgamma-azidoanilide photoaffinity labeling. Endocrine 1998;8:201–209.
Melson GL, Chase LR, Aurbach GD. Parathyroid hormone-sensitive adenyl cyclase in isolated renal tubules. Endocrinology 1970;86:511–518.
Chase LR, Fedak SA, Aurbach GD. Activation of skeletal adenyl cyclase by parathyroid hormone in vitro. Endocrinology 1969;84:761–768.
Civitelli R, Reid IR, Westbrook S, Avioli LV, Hruska KA. PTH elevates inositol polyphosphates and diacylglycerol in a rat osteoblast-like cell line. Am J Physiol 1988;255:E660-E667.
Dunlay R, Hruska K. PTH receptor coupling to phospholipase C is an alternate pathway of signal transduction in bone and kidney. Am J Physiol 1990;258:F223–F231.
Gupta A, Martin KJ, Miyauchi A, Hruska KA. Regulation of cytosolic calcium by parathyroid hormone and oscillations of cytosolic calcium in fibroblasts from normal and pseudohypoparathyroid patients. Endocrinology 1991;128:2825–2836.
Civitelli R, Martin TJ, Fausto A, Gunsten SL, Hruska KA, Avioli LV. Parathyroid hormone-related peptide transiently increases cytosolic calcium in osteoblast-like cells: comparison with parathyroid hormone. Endocrinology 1989;125:1204–1210.
Reid IR, Civitelli R, Halstead LR, Avioli LV, Hruska KA. Parathyroid hormone acutely elevates intracellular calcium in osteoblastlike cells. Am J Physiol 1987;253:E45-E51.
Yamaguchi DT, Hahn TJ, Iida-Klein A, Kleeman CR, Muallem S. Parathyroid hormone-activated calcium channels in an osteoblast-like clonal osteosarcoma cell line. J Biol Chem 1987;262:7711–7718.
Norris EH. Anatomical evidence of prenatal function of the human parathyroid glands. Anat Rec 1946; 96:129–141.
Parfitt AM. Parathyroid growth: normal and abnormal. In: Bilezikian JP, Marcus R, Levine MA, eds. The Parathyroids: Basic and Clinical Concepts. Raven Press, New York, 1994, pp. 373–405.
Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium and lactation. Endocr Rev 1997;18:832–872
Kovacs CS, Lanske B, Hunzelman JL, Guo J, Karaplis AC, Kronenberg HM. Parathyroid hormonerelated peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc Natl Acad Sci USA 1996;93:15,233–15,238.
Kovacs CS, Manley NR, Moseley JM, Martin TJ, Kronenberg HM. Fetal parathyroids are not required to maintain placental calcium transport. J Clin Invest 2001;107:1007–1015.
Akerstrom G, Grimelius L, Johansson H, Lundqvist H, Pertoft H, Bergstrom R. The parenchymal cell mass in normal human parathyroid glands. Acta Pathol Microbiol Scand [A] 1981;89:367–375.
Wang Q, Palnitkar S, Parfitt AM. The basal rate of cell proliferation in normal human parathyroid tissue: implications for the pathogenesis of hyperparathyroidism. Clin Endocrinol (Oxf) 1997;46:343–349.
Wright N, Alison M. The Biology of Epithelial Cell Populations. Clarendon Press, Oxford, 1984.
Ahonen P. Autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED): autosomal recessive inheritance. Clin Genet 1985;27:535–542.
Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990;322:1829–1836.
Scott HS, Heino M, Peterson P, et al. Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins. Mol Endocrinol 1998;12:1112–1119.
Obermayer-Straub P, Manns MP. Autoimmune polyglandular syndromes. Baillieres Clin Gastroenterol 1998;12:293–315.
Greig F, Paul E, DiMartino-Nardi J, Saenger P. Transient congenital hypoparathyroidism: resolution and recurrence in chromosome 22q11 deletion. J Pediatr 1996;128:563–567.
Hur H, Kim YJ, Noh CI, Seo JW, Kim MH. Molecular genetic analysis of the DiGeorge syndrome among Korean patients with congenital heart disease. Mol Cells 1999;9:72–77.
Monaco G, Pignata C, Rossi E, et al. DiGeorge anomaly associated with 10p deletion. Am J Med Genet 1991;19:215–216.
Daw SC, Taylor C, Kraman M, et al. A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat Genet 1996;13:458–460.
Yamagishi H, Garg V, Matsuoka R, Thomas T, Srivastava D. A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Science 1999;283:1158–1161.
Van Esch H, Groenen P, Nesbit MA, et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature 2000;406:419–422.
Thakker RV. The molecular genetics of hypoparathyroidism. In: Bilezikian JP, Marcus R, Levine MA, eds. The Parathyroids: Basic and Clinical Concepts. Academic Press, San Diego, CA, 2001, pp. 779–790.
Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM. Mutation of the signal peptideencoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. J Clin Invest 1990;86:1084–1087.
Karaplis AC, Lim SK, Baba H, Arnold A, Kronenberg HM. Inefficient membrane targeting, translocation, and proteolytic processing by signal peptidase of a mutant preproparathyroid hormone protein. J Biol Chem 1995;270:1629–1635.
Sunthornthepvarakul T, Churesigaew S, Ngowngarmratana S. A novel mutation of the signal peptide of the preproparathyroid hormone gene associated with autosomal recessive familial isolated hypoparathyroidism. J Clin Endocrinol Metab 1999;84:3792–3796.
Parkinson DB, Thakker RV. A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism. Nat Genet 1992;1:149–152.
Pearce SH, Williamson C, Kifor O, et al. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor [see comments]. N Engl J Med 1996;335:1115–1122.
Bai M, Quinn S, Trivedi S, et al. Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor. J Biol Chem 1996;271:19,537–19,545.
Chou YH, Pollak MR, Brandi ML, et al. Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia. Am J Hum Genet 1995;56:1075–1079.
Pollak MR, Chou YH, Marx SJ, et al. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. J Clin Invest 1994;93:1108–1112.
de la Chapelle A., Herra R, Kiovisto M, Aula P. A deletion in chromosome 22 can cause DiGeorge syndrome. Hum Genet 1981;57:253–256.
Kelley RI, Zackai FH, Emanuel BS. The association of the DiGeorge anomalad with partial monosomy of chromosome 22. J Pediatr 1982;101:197.
Driscoll DA, Budarf ML, Emanuel BS. A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11. Am J Hum Genet 1991;50:924.
Matsuoka R, Kimura M, Scambler PJ, et al. Molecular and clinical study of 183 patients with conotruncal anomaly face syndrome. Hum Genet 1998;103:70–80.
Berend SA, Spikes AS, Kashork CD, et al. Dual-probe fluorescence in situ hybridization assay for detecting deletions associated with VCFS/DiGeorge syndrome I and DiGeorge syndrome II loci. Am J Med Genet 2000;91:313–317.
Scambler PJ. The 22q11 deletion syndromes. Hum Mol Genet 2000;9:2421–2426.
Lai MMR, Scriven PN, Ball C, Berry AC. Simultaneous partial monosomy 10p and trisomy 5q in a case of hypoparathyroidism. J Med Genet 1992;29:586–588.
Kelly D, Goldberg R, Wilson D, et al. Confirmation that the velo-cardio-facial syndrome is associated with haplo-insufficiency of genes at chromosome 22q11. Am J Med Genet 1993;45:308–312.
Shprintzen RJ. Velocardiofacial syndrome and DiGeorge sequence. J Med Genet 1994;31:423–424.
Wilson DI, Cross IE, Goodship JA, et al. DiGeorge syndrome with isolated aortic coarctation and isolated ventricular septal defect in three sibs with a 22q11 deletion of maternal origin. Br Heart J 1991;66: 308–312.
De Silva D, Duffty P, Booth P, Auchterlonie I, Morrison N, Dean JC. Family studies in chromosome 22q11 deletion: further demonstration of phenotypic heterogeneity. Clin Dysmorphol 1995;4:294–303.
Lindsay EA, Botta A, Jurecic V, et al. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 1999;401:379–383.
Guris DL, Fantes J, Tara D, Druker BJ, Imamoto A. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Nat Genet 2001;27:293–298.
Manley NR, Capecchi MR. The role ofHoxa-3 in mouse thymus and thyroid development. Development 1995;121:1989–2003.
Lindsay EA, Vitelli F, Su H, et al. Tbx 1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 2001;410:97–101.
Jerome LA, Papaioannou VE. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx l . Nat Genet 2001;27:286–291.
Manley NR, Capecchi MR. Hox group 3 paralogs regulate the development and migration of the thymus, thyroid, and parathyroid glands. Dev Biol 1998;195:1–15.
Barakat AY, D’Albora JB, Martin MM, Jose PA. Familial nephrosis, nerver deafness, and hypoparathyroidism. J Pediatr 1977;91:61–64.
Lakshmanan G, Lieuw KH, Lim KC, et al. Localization of distant urogenital system-, central nervous system-, and endocardium-specific transcriptional regulatory elements in the GATA-3 locus. Mol Cell Biol 1999;19:1558–568.
Debacker C, Catala M, Labastie MC. Embryonic expression of the human GATA-3 gene. Mech Dev 1999;85:183–187.
Pandolfi PP, Roth ME, Karis A, et al. Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis. Nat Genet 1995;11:40–44.
Gunther T, Chen ZF, Kim J, et al. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature 2000;406:199–203.
Hosoya T, Takizawa K, Nitta K, Hotta Y. Glial cells missing: a binary switch between neuronal and glial determination in Drosophila. Cell 1995;82:1025–1036.
Wegner M, Riethmacher D. Chronicles of a switch hunt: gcm genes in development. Trends Genet 2001; 17:286–290.
Kim J, Jones BW, Zock C, et al. Isolation and characterization of mammalian homologs of the Drosophila gene glial cells missing. Proc Natl Acad Sci USA 1998;95:12,364–12,369.
Jones BW, Fetter RD, Tear G, Goodman CS. Glial cells missing: a genetic switch that controls glial versus neuronal fate. Cell 1995;82:1013–1023.
Altshuller Y, Copeland NG, Gilbert DJ, Jenkins NA, Frohman MA. Gcm1, a mammalian homolog of Drosophila glial cells missing. FEBS Lett 1996;393:201–204.
Kammerer M, Pirola B, Giglio S, Giangrande A. GCMB, a second human homolog of the fly glide/gcm gene. Cytogenet Cell Genet 1999;84:43–47.
Kanemura Y, Hiraga S, Arita N, et al. Isolation and expression analysis of a novel human homologue of the Drosophila glial cells missing (gcm) gene. FEBS Lett 1999;442:151–156.
Schreiber J, Riethmacher-Sonnenberg E, Riethmacher D, et al. Placental failure in mice lacking the mammalian homolog of glial cells missing, GCMa. Mol Cell Biol 2000;20:2466–2474.
Ding CL, Buckingham B, Levine MA. Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB. J Clin Invest 2001;108:1215–1220.
Thakker RV. Molecular basis of PTH underexpression. In: Bilezikian JP, Raisz LG, Rodan GA, eds. Principles of Bone Biology. Academic Press, San Diego, CA, 1996, pp. 837–851.
Franceschini P, Testa A, Bogetti G, et al. Kenny-Caffey syndrome in two sibs born to consanguineous parents: evidence for an autosomal recessive variant. Am J Med Genet 1992;42:112–116.
Sanjad SA, Sakati NA, Abu-Osba YK, Kaddoura R, Milner RD. A new syndrome of congenital hypoparathyroidism, severe growth failure, and dysmorphic features. Arch Dis Child 1991;66:193–196.
Diaz GA, Gelb BD, Ali F, et al. Sanjad-Sakati and autosomal recessive Kenny-Caffey syndromes are allelic: evidence for an ancestral founder mutation and locus refinement. Am J Med Genet 1999;85: 48–52.
Kelly TE, Blanton S, Saif R, Sanjad SA, Sakati NA. Confirmation of the assignment of the Sanjad-Sakati (congenital hypoparathyroidism) syndrome (OMIM 241410) locus to chromosome 1q42–43. J Med Genet 2000;37:63–64.
Dahlberg PJ, Borer WZ, Newcomer KL, Yutac WR. Autosomal or X-linked recessive syndrome of congenital lymphedema, hypoparathyroidism, nephropathy, prolapsing mitral valve, and brachytelephalangy. Am J Med Genet 1983;16:99–104.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Humana Press Inc.
About this chapter
Cite this chapter
Levine, M.A. (2002). Genetic Control of Parathyroid Gland Development and Molecular Insights into Hypoparathyroidism. In: Eugster, E.A., Pescovitz, O.H. (eds) Developmental Endocrinology. Contemporary Endocrinology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-156-5_8
Download citation
DOI: https://doi.org/10.1007/978-1-59259-156-5_8
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-4684-9663-5
Online ISBN: 978-1-59259-156-5
eBook Packages: Springer Book Archive