HGNC Approved Gene Symbol:PTH
Cytogenetic location:11p15.3 Genomic coordinates(GRCh38) :11:13,492,054-13,496,181 (from NCBI)
The sequences of parathyrin and of proparathyrin have been determined, as well as the nucleotide sequence of the PTH gene (Baxter et al., 1977;Reis et al., 1990).
The human PTH gene consists of 3 exons (Goswami et al., 2004). Exon 1 is untranslated, exon 2 encodes a 25-amino acid signal peptide and part of the prohormone, and exon 3 encodes the remaining part of the prohormone (6 amino acids) and the whole PTH molecule (84 amino acids). In humans, the terminal region of exon 3 consisting of 351 nucleotides remains untranslated (Vasicek et al., 1983;Reis et al., 1990).
Using a cDNA probe of the parathyroid hormone gene,Antonarakis et al. (1983) found a common PstI RFLP 3-prime to the PTH gene in all ethnic groups studied. Family linkage studies were then performed with this RFLP and with RFLPs related to the hemoglobin-beta (HBB;141900) and insulin (INS;176730) loci. They found that PTH and HBB are closely linked (recombination fraction, 0.07; confidence limits, 0.05-0.10; lod score, 4.63). Furthermore, HBB lies between PTH and INS. They estimated the interval between HBB and INS as 11 cM and the length of 11p as about 50 cM.
By in situ hybridization of meiotic pachytene bivalents,Chaganti et al. (1985) arrived at the following localizations: PTH (not previously assigned regionally), 11p11.21; HBB, 11p11.22; HRAS (190020), 11p14.1 and INS, 11p14.1.
By use of RFLPs that map to 11p,Raizis et al. (1985) detected mitotic recombination as the mechanism of homozygosity in a Wilms tumor. Their findings showed that insulin and beta-globin had come to homozygosity in the tumor but PTH remained heterozygous. Thus, PTH must be proximal to 11p13, the cytologically determined site of the Wilms tumor 'gene.' Using RFLP markers,Holm et al. (1985) concluded that PTH and CALC1 (114130) are very closely linked. No recombination was found in a large number of opportunities. A lod score of 27.3 was obtained with a maximum likelihood recombination fraction of 0.002.
By in situ hybridizationZabel et al. (1985) assigned PTH to 11p15 along with INS, HRAS, and HBB. Their result was inconsistent with earlier localizations. In most parts of 11p, male recombination is greater than female recombination, contrary to the usual finding.
Tonoki et al. (1991) concluded from studies using RFLPs and gene dosage in a patient with the Beckwith-Wiedemann syndrome (130650) accompanied with a chromosome abnormality that PTH is located proximal to 11p15.4 in the region 11p15.3-p15.1, most likely near the border of bands 11p15.4 and 11p15.3.
Lalley et al. (1987) mapped the gene for parathyroid hormone to mouse chromosome 7.
By transfection of C-terminal deletion mutant preproPTH in COS-7 cells,Lim et al. (1992) showed that the C terminus of PTH was necessary for transport, efficient prosequence cleavage, and secretion.
Hendy et al. (1995) stated that the mRNA for PTH, in addition to encoding the 84 amino acids of the mature peptide, encodes a 'pre' sequence of 25 amino acids and a basic 'pro' hexapeptide. They reported experiments indicating that furin (PACE;136950) is the most effective convertase in processing proPTH to PTH. Northern blot analysis and in situ hybridization showed that furin and preproPTH mRNA are coexpressed in the parathyroid gland, whereas other prohormone convertases PC1 (162150), PC2 (162151), and PC5 (600488) are not and PACE4 (167405) is expressed only at very low levels.Hendy et al. (1995) concluded that furin is the enzyme responsible for the physiologic processing of proPTH to PTH.
Adams et al. (1998) used a photoaffinity crosslinking approach to elucidate the nature of the bimolecular interaction of PTH with human PTHR1. They found arg186 to be of critical importance to the interaction of PTHR1 with the PTH 125I-K13 contact domain (Zhou et al., 1997): modification of arg186 to either lysine or alanine does not modify receptor avidity or signal transduction by the receptor, but eliminates crosslinking to 125I-K13.
PTH stimulates bone formation to increase bone mass and strength in rats and humans.Brommage et al. (1999) studied the skeletal effects of recombinant human PTH-(1-34)(rhPTH-(1-34)) in monkeys, as monkey bone remodeling and structure are similar to those in human bone. Recombinant human PTH-(1-34) treatment did not influence serum ionized Ca levels or urinary Ca excretion, but depressed endogenous PTH while increasing serum calcitriol levels. Compared to that in the ovariectomized group, the higher dose of rhPTH-(1-34) increased spine bone mineral density by 14.3%, whole body bone mineral content by 8.6%, and proximal tibia bone mineral density by 10.8%. Subregion analyses suggested that the anabolic effect of rhPTH-(1-34) on the proximal tibia was primarily in cancellous bone. Similar but less dramatic effects on bone mineral density were observed with the lower dose of rhPTH-(1-34). Daily subcutaneous rhPTH-(1-34) treatment for 1 year increased bone mineral density in ovariectomized monkeys without inducing sustained hypercalcemia or hypercalciuria.
Purroy and Spurr (2002) reviewed the cell biology and molecular genetics of calcium sensing in bone cells.
Parathyroid adenomas are benign clonal neoplastic growths, some of which have been shown to have tumor-specific restriction fragment abnormalities involving the PTH locus (Arnold et al., 1988). In a case of parathyroid adenoma bearing restriction fragment abnormalities,Arnold et al. (1989) showed that a DNA rearrangement had occurred in the PTH locus; that the rearrangement separated the 5-prime flanking region of the PTH gene from its coding exons, conceivably placing a newly adjacent gene under the influence of PTH regulatory elements; that the DNA that recombined with PTH normally maps to 11q13, the chromosomal location of several oncogenes and the gene for MEN I (131100); and that the rearrangement was a reciprocal, conservative recombination of the locus on 11q13 (designated D11S287) with PTH (on 11p15).Nussbaum et al. (1990) demonstrated that the ovarian carcinoma in a patient with hypercalcemia and ectopic secretion of PTH had both DNA amplification and rearrangement in the upstream regulatory region of the PTH gene.
Cui et al. (1989) estimated the frequency of recombination between the PTH locus and the G-gamma-globin locus (HBG2;142250) by typing more than 700 single-sperm samples from 2 males. The typing technique involved PCR and allele-specific oligonucleotide hybridization. They arrived at a maximum likelihood recombination frequency of 0.16 (95% confidence interval, 0.13-0.19). They suggested that with current technology and a sample size of 1,000 sperm, recombination fractions down to about 0.009 can be estimated with statistical reliability; with a sample size of 5,000 sperm, this value dropped to about 0.004. Reasonable technologic improvements could be expected to result in detection of recombination frequencies less than 0.001.
Familial Isolated Hypoparathyroidism 1
In a patient from a family with autosomal dominant hypoparathyroidism (FIH1;146200),Arnold et al. (1990) identified heterozygosity for a missense mutation in the PTH gene (168450.0001). Functional studied demonstrated inefficient processing of the mutant protein.
In 3 sibs from a consanguineous family with isolated hypoparathyroidism,Parkinson and Thakker (1992) identified homozygosity for a splice site mutation in the PTH gene (168450.0002).
In affected members of a consanguineous kindred who presented with neonatal hypocalcemic seizures and were found to have isolated hypoparathyroidism,Sunthornthepvarakul et al. (1999) identified homozygosity for a missense mutation (168450.0003) in the PTH gene.
Primary Hyperparathyroidism
Au et al. (2008) reported the case of a parathyroid adenoma in which there was loss of heterozygosity for the normal allele and secretion of a biologically active N-terminal PTH fragment, which was truncated due to a nonsense mutation in the PTH gene (168450.0004).
Exclusion Studies
Goswami et al. (2004) sought PTH mutations in 51 patients with sporadic idiopathic hypoparathyroidism. No mutations were observed in the segment of the PTH gene coding for the signal peptide, prohormone, or the 3-prime untranslated region region. However, 3 previously described single-nucleotide polymorphisms (SNPs) were observed. There was no significant difference in the frequency of occurrence of these SNPs between the patient and the control groups. The authors concluded that in patients with sporadic idiopathic hypoparathyroidism, neither the clinical manifestations nor the biochemical indexes of the disease are related to the occurrence of mutations or SNPs in the PTH gene.
Miao et al. (2002) compared the skeletal development of newborn mice lacking either Pth, Pth-related peptide (PTHLH;168470), or both peptides. Pth-deficient mice were dysmorphic but viable. They demonstrated diminished cartilage matrix mineralization, decreased neovascularization with reduced expression of angiopoietin-1 (601667), and reduced metaphyseal osteoblasts and trabecular bone. Mice lacking Pthlh died at birth with dyschondroplasia. Compound mutants displayed the combined cartilaginous and osseous defects of both single mutants, indicating that both hormones are required to achieve normal fetal skeletal morphogenesis, and they demonstrated an essential function of Pth at the cartilage-bone interface.
Healy et al. (2005) administered human PTH over 48 hours to wildtype mice and observed a 15% reduction in renal vitamin D receptor (VDR;601769) levels (p less than 0.03). When the authors similarly administered PTH to Cyp27b1 (609506)-null mice, which are incapable of endogenously producing vitamin D hormone, they observed a 29% reduction in VDR levels (p less than 0.001).Healy et al. (2005) concluded that PTH is a potent downregulator of VDR expression in vivo.
Xue et al. (2005) compared mice with targeted disruption of the Pth or 25-hydroxyvitamin D3-1-alpha-hydroxylase (CYP27B1;609506) genes to the double-null mutants. Although Pth-null and Cyp27b1-null mice displayed only moderate hypocalcemia, Pth/Cyp27b1 double-null mice died of tetany with severe hypocalcemia by 3 weeks of age. At 2 weeks, Pth-null mice exhibited only minimal dysmorphic changes, whereas Cyp27b1-null mice showed epiphyseal dysgenesis, and Pth/Cyp27b1 double-mutants showed severe epiphyseal dysgenesis. Although reduced osteoblastic bone formation was seen in both mutants, Pth deficiency caused only a slight reduction in long bone length but a marked reduction in trabecular bone volume, whereas Cyp27b1 ablation caused a smaller reduction in trabecular bone volume but a significant decrease in bone length. The authors concluded that PTH plays a predominant role in appositional bone growth, whereas 1,25(OH)2D3 acts predominantly on endochondral bone formation. Although PTH and 1,25(OH)2D3 independently, but not additively, regulate osteoclastic bone resorption, they do affect the renal calcium transport pathway cooperatively. Consequently, PTH and 1,25(OH)2D3 exhibited discrete and collaborative roles in modulating skeletal and calcium homeostasis, andXue et al. (2005) hypothesized that loss of the renal component of calcium conservation may be the major factor contributing to the lethal hypocalcemia in double mutants.
Mullersman et al. (1992) described 2 new RFLPs within the PTH locus. Both were detectable by a PCR-based assay.
In a patient from a family (family D) with autosomal dominant hypoparathyroidism (FIH1;146200), earlier reported byAhn et al. (1986),Arnold et al. (1990) identified heterozygosity for a T-to-C transition in exon 2 of the PTH gene, resulting in a cys18-to-arg (C18R) substitution in the 31-amino acid prepro-sequence of parathyroid hormone, disrupting the hydrophobic core of the signal sequence. The patient's father, who was clinically unaffected but had a subnormal PTH and urinary cAMP responses upon induction of hypocalcemia, was also heterozygous for the mutation, which was not found in unaffected family members. Because the hydrophobic core is required by secreted proteins for efficient translocation across the endoplasmic reticulum, the mutant protein would be expected to show inefficient processing, which indeedArnold et al. (1990) demonstrated.
In HEK293 cells transfected with C18R-mutant preproPTH cDNA,Datta et al. (2007) demonstrated that the expressed mutant hormone was trapped intracellularly, predominantly in the endoplasmic reticulum (ER), resulting in apoptosis. The C18R-expressing cells also showed marked upregulation of the ER stress-responsive hormones BIP (HSPA5;138120) and PERK (EIF2AK3;604032) and the proapoptotic transcription factor CHOP (DDIT3;126337). When C18R-mutant PTH was expressed in the presence of the pharmacologic chaperone 4-phenylbutyric acid, intracellular accumulation was reduced and normal secretion was restored.Datta et al. (2007) suggested that ER stress-induced cell death is the underlying mechanism for autosomal dominant hypoparathyroidism.
In 2 sisters and a brother with isolated hypoparathyroidism (FIH1;146200), the offspring of a first-cousin marriage,Parkinson and Thakker (1992) identified homozygosity for a G-to-C transversion at the first nucleotide of intron 2 of the parathyroid hormone gene. The mutation was detected by restriction enzyme cleavage with DdeI. Both parents were heterozygous and unrelated normal individuals were homozygous for the wildtype allele. Defects in mRNA splicing were investigated by the detection of illegitimate transcription of the PTH gene in lymphoblastoid cells. The mutation resulted in exon skipping with loss of exon 2, which encodes the initiation codon and the signal peptide, thereby causing parathyroid hormone deficiency.
In a patient with neonatal hypocalcemic seizures (FIH1;146200), whose parents were consanguineous,Sunthornthepvarakul et al. (1999) identified a T-to-C transition in exon 2 of the PTH gene, resulting in a ser23-to-pro (S23P) substitution in the 25-amino acid prepro-PTH signal peptide. Serum calcium was 1.5 mmol/L (normal, 2.0-2.5); phosphate was 3.6 mmol/L (normal, 0.9-1.5). A few years later, 2 younger sisters and her niece presented with neonatal hypocalcemic seizures. Their intact PTH levels were undetectable during severe hypocalcemia. Genomic DNA from the proposita was sequenced in all exons of the prepro-PTH gene. Genotyping of family members was carried out by identification of a new MspI site created by the mutation. Only affected family members were homozygous for the mutant allele, whereas the parents were heterozygous, supporting autosomal recessive inheritance. As this mutation is at the -3 position in the signal peptide of the prepro-PTH gene, the authors hypothesized that the prepro-PTH mutant might not be cleaved by signal peptidase at the normal position, and it might be degraded in rough endoplasmic reticulum.
In the parathyroid adenoma (see145000) of a 59-year-old woman with hypercalcemia but undetectable serum PTH levels, in which microarray analysis showed upregulated PTH expression despite negative immunohistochemistry for PTH,Au et al. (2008) identified a 247C-T transition in the PTH gene, resulting in an arg83-to-ter (R83X) substitution and predicting premature termination after 52 amino acids in the secreted PTH peptide. No wildtype sequence was detected in tumor DNA, although analysis of peripheral blood leukocyte DNA revealed heterozygosity for the mutation; loss of heterozygosity analysis showed that the wildtype PTH allele had been deleted in the tumor. The authors confirmed that an N-terminal PTH fragment was produced by tumor cells cultured ex vivo. Noting thatLim et al. (1992) had previously studied the R83X mutation in vitro and demonstrated impairment of translocation across the ER, cleavage of pro-PTH, and secretion of PTH,Au et al. (2008) stated that this case provides evidence that an endogenously produced N-terminal PTH fragment can be biologically active.
Adams, A. E., Bisello, A., Chorev, M., Rosenblatt, M., Suva, L. J.Arginine 186 in the extracellular N-terminal region of the human parathyroid hormone 1 receptor is essential for contact with position 13 of the hormone. Molec. Endocr. 12: 1673-1683, 1998. [PubMed:9817594,related citations] [Full Text]
Ahn, T. G., Antonarakis, S. E., Kronenberg, H. M., Igarashi, T., Levine, M. A.Familial isolated hypoparathyroidism: a molecular genetic analysis of 8 families with 23 affected persons. Medicine 65: 73-81, 1986. [PubMed:3005800,related citations]
Antonarakis, S. E., Phillips, J. A., III, Mallonee, R. L., Kazazian, H. H., Jr., Fearon, E. R., Waber, P. G., Kronenberg, H. M., Ullrich, A., Meyers, D. A.Beta-globin locus is linked to the parathyroid hormone (PTH) locus and lies between the insulin and PTH loci in man. Proc. Nat. Acad. Sci. 80: 6615-6619, 1983. [PubMed:6314332,related citations] [Full Text]
Arnold, A., Horst, S. A., Gardella, T. J., Baba, H., Levine, M. A., Kronenberg, H. M.Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. J. Clin. Invest. 86: 1084-1087, 1990. [PubMed:2212001,related citations] [Full Text]
Arnold, A., Kim, H. G., Gaz, R. D., Eddy, R. L., Fukushima, Y., Byers, M. G., Shows, T. B., Kronenberg, H. M.Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J. Clin. Invest. 83: 2034-2040, 1989. [PubMed:2723071,related citations] [Full Text]
Arnold, A., Staunton, C. E., Kim, H. G., Gaz, R. D., Kronenberg, H. M.Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. New Eng. J. Med. 318: 658-662, 1988. [PubMed:3344017,related citations] [Full Text]
Au, A. Y. M., McDonald, K., Gill, A., Sywak, M., Diamond, T., Conigrave, A. D., Clifton-Bligh, R. J.PTH mutation with primary hyperparathyroidism and undetectable intact PTH. New Eng. J. Med. 359: 1184-1186, 2008. [PubMed:18784115,related citations] [Full Text]
Baxter, J. D., Seeburg, P. H., Shine, J., Martial, J. A., Goodman, H. M.DNA sequence of a human gene coding for a polypeptide hormone. (Abstract) Clin. Res. 25: 514A only, 1977.
Brommage, R., Hotchkiss, C. E., Lees, C. J., Stancill, M. W., Hock, J. M., Jerome, C. P.Daily treatment with human recombinant parathyroid hormone-(1-34), LY333334, for 1 year increases bone mass in ovariectomized monkeys. J. Clin. Endocr. Metab. 84: 3757-3763, 1999. [PubMed:10523026,related citations] [Full Text]
Chaganti, R. S. K., Jhanwar, S. C., Antonarakis, S. E., Hayward, W. S.Germ-line chromosomal localization of genes in chromosome 11p linkage: parathyroid hormone, beta-globin, c-Ha-ras-1, and insulin. Somat. Cell Molec. Genet. 11: 197-202, 1985. [PubMed:3885418,related citations] [Full Text]
Cui, X. F., Li, H. H., Goradia, T. M., Lange, K., Kazazian, H. H., Jr., Galas, D., Arnheim, N.Single-sperm typing: determination of genetic distance between the G-gamma-globin and parathyroid hormone loci by using the polymerase chain reaction and allele-specific oligomers. Proc. Nat. Acad. Sci. 86: 9389-9393, 1989. [PubMed:2574460,related citations] [Full Text]
Datta, R., Waheed, A., Shah, G. N., Sly, W. S.Signal sequence mutation in autosomal dominant form of hypoparathyroidism induces apoptosis that is corrected by a chemical chaperone. Proc. Nat. Acad. Sci. 104: 19989-19994, 2007. [PubMed:18056632,images,related citations] [Full Text]
Goswami, R., Mohapatra, T., Gupta, N., Rani, R., Tomar, N., Dikshit, A., Sharma, R. K.Parathyroid hormone gene polymorphism and sporadic idiopathic hypoparathyroidism. J. Clin. Endocr. Metab. 89: 4840-4845, 2004. [PubMed:15472173,related citations] [Full Text]
Habener, J. F., Rosenblatt, M., Kemper, B., Kronenberg, H. M., Rich, A., Potts, J. T., Jr.Pre-proparathyroid hormone: amino acid sequence, chemical synthesis, and some biological studies of the precursor region. Proc. Nat. Acad. Sci. 75: 2616-2620, 1978. [PubMed:96437,related citations] [Full Text]
Healy, K. D., Vanhooke, J. L., Prahl, J. M., DeLuca, H. F.Parathyroid hormone decreases renal vitamin D receptor expression in vivo. Proc. Nat. Acad. Sci. 102: 4724-4728, 2005. [PubMed:15769857,images,related citations] [Full Text]
Hendy, G. N., Bennett, H. P. J., Gibbs, B. F., Lazure, C., Day, R., Seidah, N. G.Proparathyroid hormone is preferentially cleaved to parathyroid hormone by the prohormone convertase furin: a mass spectrometric study. J. Biol. Chem. 270: 9517-9525, 1995. [PubMed:7721880,related citations] [Full Text]
Holm, T., O'Connell, P., Leppert, M., Callahan, P., White, R.Parathyroid hormone and calcitonin are tightly linked and have been placed on the genetic map of chromosome 11p. (Abstract) Am. J. Hum. Genet. 37: A156 only, 1985.
Kronenberg, H. M., McDevitt, B. E., Majzoub, J. A., Nathans, J., Sharp, P. A., Potts, J. T., Jr., Rich, A.Cloning and nucleotide sequence of DNA coding for bovine preproparathyroid hormone. Proc. Nat. Acad. Sci. 76: 4981-4985, 1979. [PubMed:388425,related citations] [Full Text]
Lalley, P. A., Sakaguchi, A. Y., Eddy, R. L., Honey, N. H., Bell, G. I., Shen, L.-P., Rutter, W. J., Jacobs, J. W., Heinrich, G., Chin, W. W., Naylor, S. L.Mapping polypeptide hormone genes in the mouse: somatostatin, glucagon, calcitonin, and parathyroid hormone. Cytogenet. Cell Genet. 44: 92-97, 1987. [PubMed:2882956,related citations] [Full Text]
Lebo, R. V., Cheung, M.-C., Bruce, B. D., Riccardi, V. M., Kao, F.-T., Kan, Y. W.Mapping parathyroid hormone, beta-globin, insulin, and LDH-A genes within the human chromosome 11 short arm by spot blotting sorted chromosomes. Hum. Genet. 69: 316-320, 1985. [PubMed:2985490,related citations] [Full Text]
Lim, S. K., Gardella, T. J., Baba, H., Nussbaum, S. R., Kronenberg, H. M.The carboxy-terminus of parathyroid hormone is essential for hormone processing and secretion. Endocrinology 131: 2325-2330, 1992. [PubMed:1425431,related citations] [Full Text]
Mayer, H., Breyel, E., Bostock, C., Schmidtke, J.Assignment of the human parathyroid hormone gene to chromosome 11. Hum. Genet. 64: 283-285, 1983. [PubMed:6885073,related citations] [Full Text]
Miao, D., He, B., Karaplis, A. C., Goltzman, D.Parathyroid hormone is essential for normal fetal bone formation. J. Clin. Invest. 109: 1173-1182, 2002. [PubMed:11994406,images,related citations] [Full Text]
Mullersman, J. E., Shields, J. J., Saha, B. K.Characterization of two novel polymorphisms at the human parathyroid hormone gene locus. Hum. Genet. 88: 589-592, 1992. [PubMed:1348047,related citations] [Full Text]
Nussbaum, S. R., Gaz, R. D., Arnold, A.Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. New Eng. J. Med. 323: 1324-1328, 1990. [PubMed:2215618,related citations] [Full Text]
Parkinson, D. B., Thakker, R. V.A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism. Nature Genet. 1: 149-152, 1992. [PubMed:1302009,related citations] [Full Text]
Purroy, J., Spurr, N. K.Molecular genetics of calcium sensing in bone cells. Hum. Molec. Genet. 11: 2377-2384, 2002. [PubMed:12351573,related citations] [Full Text]
Raizis, A. M., Becroft, D. M., Shaw, R. L., Reeve, A. E.A mitotic recombination in Wilms tumor occurs between the parathyroid hormone locus and 11p13. Hum. Genet. 70: 344-346, 1985. [PubMed:2991119,related citations] [Full Text]
Reis, A., Hecht, W., Groger, R., Bohm, I., Cooper, D. N., Lindenmaier, W., Mayer, H., Schmidtke, J.Cloning and sequence analysis of the human parathyroid hormone gene region. Hum. Genet. 84: 119-124, 1990. [PubMed:2298446,related citations] [Full Text]
Schmidtke, J., Pape, B., Krengel, U., Langenbeck, U., Cooper, D. N., Breyel, E., Mayer, H.Restriction fragment length polymorphisms at the human parathyroid hormone gene locus. Hum. Genet. 67: 428-431, 1984. [PubMed:6092261,related citations] [Full Text]
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. Endocr. Metab. 84: 3792-3796, 1999. [PubMed:10523031,related citations] [Full Text]
Tonoki, H., Narahara, K., Matsumoto, T., Niikawa, N.Regional mapping of the parathyroid hormone gene (PTH) by cytogenetic and molecular studies. Cytogenet. Cell Genet. 56: 103-104, 1991. [PubMed:1672845,related citations] [Full Text]
Vasicek, T. J., McDevitt, B. E., Freeman, M. W., Fennick, B. J., Hendy, G. N., Potts, J. T., Jr., Rich, A., Kronenberg, H. M.Nucleotide sequence of the human parathyroid hormone gene. Proc. Nat. Acad. Sci. 80: 2127-2131, 1983. [PubMed:6220408,related citations] [Full Text]
Xue, Y., Karaplis, A. C., Hendy, G. N., Goltzman, D., Miao, D.Genetic models show that parathyroid hormone and 1,25-dihydroxyvitamin D(3) play distinct and synergistic roles in postnatal mineral ion homeostasis and skeletal development. Hum. Molec. Genet. 14: 1515-1528, 2005. [PubMed:15843402,related citations] [Full Text]
Zabel, B. U., Kronenberg, H. M., Bell, G. I., Shows, T. B.Chromosome mapping of genes on the short arm of human chromosome 11: parathyroid hormone gene is at 11p15 together with the genes for insulin, c-Harvey-ras 1, and beta-hemoglobin. Cytogenet. Cell Genet. 39: 200-205, 1985. [PubMed:3899525,related citations] [Full Text]
Zhou, A. T., Bessalle, R., Bisello, A., Nakamoto, C., Rosenblatt, M., Suva, L. J., Chorev, M.Direct mapping of an agonist-binding domain within the parathyroid hormone/parathyroid hormone-related protein receptor by photoaffinity crosslinking. Proc. Nat. Acad. Sci. 94: 3644-3649, 1997. [PubMed:9108031,images,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: PTH
SNOMEDCT: 36348003; ICD10CM: E21.0; ICD9CM: 252.01;
Cytogenetic location: 11p15.3 Genomic coordinates(GRCh38) : 11:13,492,054-13,496,181(from NCBI)
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 11p15.3 | Hypoparathyroidism, familial isolated 1 | 146200 | Autosomal dominant; Autosomal recessive | 3 |
The sequences of parathyrin and of proparathyrin have been determined, as well as the nucleotide sequence of the PTH gene (Baxter et al., 1977; Reis et al., 1990).
The human PTH gene consists of 3 exons (Goswami et al., 2004). Exon 1 is untranslated, exon 2 encodes a 25-amino acid signal peptide and part of the prohormone, and exon 3 encodes the remaining part of the prohormone (6 amino acids) and the whole PTH molecule (84 amino acids). In humans, the terminal region of exon 3 consisting of 351 nucleotides remains untranslated (Vasicek et al., 1983; Reis et al., 1990).
Using a cDNA probe of the parathyroid hormone gene, Antonarakis et al. (1983) found a common PstI RFLP 3-prime to the PTH gene in all ethnic groups studied. Family linkage studies were then performed with this RFLP and with RFLPs related to the hemoglobin-beta (HBB; 141900) and insulin (INS; 176730) loci. They found that PTH and HBB are closely linked (recombination fraction, 0.07; confidence limits, 0.05-0.10; lod score, 4.63). Furthermore, HBB lies between PTH and INS. They estimated the interval between HBB and INS as 11 cM and the length of 11p as about 50 cM.
By in situ hybridization of meiotic pachytene bivalents, Chaganti et al. (1985) arrived at the following localizations: PTH (not previously assigned regionally), 11p11.21; HBB, 11p11.22; HRAS (190020), 11p14.1 and INS, 11p14.1.
By use of RFLPs that map to 11p, Raizis et al. (1985) detected mitotic recombination as the mechanism of homozygosity in a Wilms tumor. Their findings showed that insulin and beta-globin had come to homozygosity in the tumor but PTH remained heterozygous. Thus, PTH must be proximal to 11p13, the cytologically determined site of the Wilms tumor 'gene.' Using RFLP markers, Holm et al. (1985) concluded that PTH and CALC1 (114130) are very closely linked. No recombination was found in a large number of opportunities. A lod score of 27.3 was obtained with a maximum likelihood recombination fraction of 0.002.
By in situ hybridization Zabel et al. (1985) assigned PTH to 11p15 along with INS, HRAS, and HBB. Their result was inconsistent with earlier localizations. In most parts of 11p, male recombination is greater than female recombination, contrary to the usual finding.
Tonoki et al. (1991) concluded from studies using RFLPs and gene dosage in a patient with the Beckwith-Wiedemann syndrome (130650) accompanied with a chromosome abnormality that PTH is located proximal to 11p15.4 in the region 11p15.3-p15.1, most likely near the border of bands 11p15.4 and 11p15.3.
Lalley et al. (1987) mapped the gene for parathyroid hormone to mouse chromosome 7.
By transfection of C-terminal deletion mutant preproPTH in COS-7 cells, Lim et al. (1992) showed that the C terminus of PTH was necessary for transport, efficient prosequence cleavage, and secretion.
Hendy et al. (1995) stated that the mRNA for PTH, in addition to encoding the 84 amino acids of the mature peptide, encodes a 'pre' sequence of 25 amino acids and a basic 'pro' hexapeptide. They reported experiments indicating that furin (PACE; 136950) is the most effective convertase in processing proPTH to PTH. Northern blot analysis and in situ hybridization showed that furin and preproPTH mRNA are coexpressed in the parathyroid gland, whereas other prohormone convertases PC1 (162150), PC2 (162151), and PC5 (600488) are not and PACE4 (167405) is expressed only at very low levels. Hendy et al. (1995) concluded that furin is the enzyme responsible for the physiologic processing of proPTH to PTH.
Adams et al. (1998) used a photoaffinity crosslinking approach to elucidate the nature of the bimolecular interaction of PTH with human PTHR1. They found arg186 to be of critical importance to the interaction of PTHR1 with the PTH 125I-K13 contact domain (Zhou et al., 1997): modification of arg186 to either lysine or alanine does not modify receptor avidity or signal transduction by the receptor, but eliminates crosslinking to 125I-K13.
PTH stimulates bone formation to increase bone mass and strength in rats and humans. Brommage et al. (1999) studied the skeletal effects of recombinant human PTH-(1-34)(rhPTH-(1-34)) in monkeys, as monkey bone remodeling and structure are similar to those in human bone. Recombinant human PTH-(1-34) treatment did not influence serum ionized Ca levels or urinary Ca excretion, but depressed endogenous PTH while increasing serum calcitriol levels. Compared to that in the ovariectomized group, the higher dose of rhPTH-(1-34) increased spine bone mineral density by 14.3%, whole body bone mineral content by 8.6%, and proximal tibia bone mineral density by 10.8%. Subregion analyses suggested that the anabolic effect of rhPTH-(1-34) on the proximal tibia was primarily in cancellous bone. Similar but less dramatic effects on bone mineral density were observed with the lower dose of rhPTH-(1-34). Daily subcutaneous rhPTH-(1-34) treatment for 1 year increased bone mineral density in ovariectomized monkeys without inducing sustained hypercalcemia or hypercalciuria.
Purroy and Spurr (2002) reviewed the cell biology and molecular genetics of calcium sensing in bone cells.
Parathyroid adenomas are benign clonal neoplastic growths, some of which have been shown to have tumor-specific restriction fragment abnormalities involving the PTH locus (Arnold et al., 1988). In a case of parathyroid adenoma bearing restriction fragment abnormalities, Arnold et al. (1989) showed that a DNA rearrangement had occurred in the PTH locus; that the rearrangement separated the 5-prime flanking region of the PTH gene from its coding exons, conceivably placing a newly adjacent gene under the influence of PTH regulatory elements; that the DNA that recombined with PTH normally maps to 11q13, the chromosomal location of several oncogenes and the gene for MEN I (131100); and that the rearrangement was a reciprocal, conservative recombination of the locus on 11q13 (designated D11S287) with PTH (on 11p15). Nussbaum et al. (1990) demonstrated that the ovarian carcinoma in a patient with hypercalcemia and ectopic secretion of PTH had both DNA amplification and rearrangement in the upstream regulatory region of the PTH gene.
Cui et al. (1989) estimated the frequency of recombination between the PTH locus and the G-gamma-globin locus (HBG2; 142250) by typing more than 700 single-sperm samples from 2 males. The typing technique involved PCR and allele-specific oligonucleotide hybridization. They arrived at a maximum likelihood recombination frequency of 0.16 (95% confidence interval, 0.13-0.19). They suggested that with current technology and a sample size of 1,000 sperm, recombination fractions down to about 0.009 can be estimated with statistical reliability; with a sample size of 5,000 sperm, this value dropped to about 0.004. Reasonable technologic improvements could be expected to result in detection of recombination frequencies less than 0.001.
Familial Isolated Hypoparathyroidism 1
In a patient from a family with autosomal dominant hypoparathyroidism (FIH1; 146200), Arnold et al. (1990) identified heterozygosity for a missense mutation in the PTH gene (168450.0001). Functional studied demonstrated inefficient processing of the mutant protein.
In 3 sibs from a consanguineous family with isolated hypoparathyroidism, Parkinson and Thakker (1992) identified homozygosity for a splice site mutation in the PTH gene (168450.0002).
In affected members of a consanguineous kindred who presented with neonatal hypocalcemic seizures and were found to have isolated hypoparathyroidism, Sunthornthepvarakul et al. (1999) identified homozygosity for a missense mutation (168450.0003) in the PTH gene.
Primary Hyperparathyroidism
Au et al. (2008) reported the case of a parathyroid adenoma in which there was loss of heterozygosity for the normal allele and secretion of a biologically active N-terminal PTH fragment, which was truncated due to a nonsense mutation in the PTH gene (168450.0004).
Exclusion Studies
Goswami et al. (2004) sought PTH mutations in 51 patients with sporadic idiopathic hypoparathyroidism. No mutations were observed in the segment of the PTH gene coding for the signal peptide, prohormone, or the 3-prime untranslated region region. However, 3 previously described single-nucleotide polymorphisms (SNPs) were observed. There was no significant difference in the frequency of occurrence of these SNPs between the patient and the control groups. The authors concluded that in patients with sporadic idiopathic hypoparathyroidism, neither the clinical manifestations nor the biochemical indexes of the disease are related to the occurrence of mutations or SNPs in the PTH gene.
Miao et al. (2002) compared the skeletal development of newborn mice lacking either Pth, Pth-related peptide (PTHLH; 168470), or both peptides. Pth-deficient mice were dysmorphic but viable. They demonstrated diminished cartilage matrix mineralization, decreased neovascularization with reduced expression of angiopoietin-1 (601667), and reduced metaphyseal osteoblasts and trabecular bone. Mice lacking Pthlh died at birth with dyschondroplasia. Compound mutants displayed the combined cartilaginous and osseous defects of both single mutants, indicating that both hormones are required to achieve normal fetal skeletal morphogenesis, and they demonstrated an essential function of Pth at the cartilage-bone interface.
Healy et al. (2005) administered human PTH over 48 hours to wildtype mice and observed a 15% reduction in renal vitamin D receptor (VDR; 601769) levels (p less than 0.03). When the authors similarly administered PTH to Cyp27b1 (609506)-null mice, which are incapable of endogenously producing vitamin D hormone, they observed a 29% reduction in VDR levels (p less than 0.001). Healy et al. (2005) concluded that PTH is a potent downregulator of VDR expression in vivo.
Xue et al. (2005) compared mice with targeted disruption of the Pth or 25-hydroxyvitamin D3-1-alpha-hydroxylase (CYP27B1; 609506) genes to the double-null mutants. Although Pth-null and Cyp27b1-null mice displayed only moderate hypocalcemia, Pth/Cyp27b1 double-null mice died of tetany with severe hypocalcemia by 3 weeks of age. At 2 weeks, Pth-null mice exhibited only minimal dysmorphic changes, whereas Cyp27b1-null mice showed epiphyseal dysgenesis, and Pth/Cyp27b1 double-mutants showed severe epiphyseal dysgenesis. Although reduced osteoblastic bone formation was seen in both mutants, Pth deficiency caused only a slight reduction in long bone length but a marked reduction in trabecular bone volume, whereas Cyp27b1 ablation caused a smaller reduction in trabecular bone volume but a significant decrease in bone length. The authors concluded that PTH plays a predominant role in appositional bone growth, whereas 1,25(OH)2D3 acts predominantly on endochondral bone formation. Although PTH and 1,25(OH)2D3 independently, but not additively, regulate osteoclastic bone resorption, they do affect the renal calcium transport pathway cooperatively. Consequently, PTH and 1,25(OH)2D3 exhibited discrete and collaborative roles in modulating skeletal and calcium homeostasis, and Xue et al. (2005) hypothesized that loss of the renal component of calcium conservation may be the major factor contributing to the lethal hypocalcemia in double mutants.
Mullersman et al. (1992) described 2 new RFLPs within the PTH locus. Both were detectable by a PCR-based assay.
In a patient from a family (family D) with autosomal dominant hypoparathyroidism (FIH1; 146200), earlier reported by Ahn et al. (1986), Arnold et al. (1990) identified heterozygosity for a T-to-C transition in exon 2 of the PTH gene, resulting in a cys18-to-arg (C18R) substitution in the 31-amino acid prepro-sequence of parathyroid hormone, disrupting the hydrophobic core of the signal sequence. The patient's father, who was clinically unaffected but had a subnormal PTH and urinary cAMP responses upon induction of hypocalcemia, was also heterozygous for the mutation, which was not found in unaffected family members. Because the hydrophobic core is required by secreted proteins for efficient translocation across the endoplasmic reticulum, the mutant protein would be expected to show inefficient processing, which indeed Arnold et al. (1990) demonstrated.
In HEK293 cells transfected with C18R-mutant preproPTH cDNA, Datta et al. (2007) demonstrated that the expressed mutant hormone was trapped intracellularly, predominantly in the endoplasmic reticulum (ER), resulting in apoptosis. The C18R-expressing cells also showed marked upregulation of the ER stress-responsive hormones BIP (HSPA5; 138120) and PERK (EIF2AK3; 604032) and the proapoptotic transcription factor CHOP (DDIT3; 126337). When C18R-mutant PTH was expressed in the presence of the pharmacologic chaperone 4-phenylbutyric acid, intracellular accumulation was reduced and normal secretion was restored. Datta et al. (2007) suggested that ER stress-induced cell death is the underlying mechanism for autosomal dominant hypoparathyroidism.
In 2 sisters and a brother with isolated hypoparathyroidism (FIH1; 146200), the offspring of a first-cousin marriage, Parkinson and Thakker (1992) identified homozygosity for a G-to-C transversion at the first nucleotide of intron 2 of the parathyroid hormone gene. The mutation was detected by restriction enzyme cleavage with DdeI. Both parents were heterozygous and unrelated normal individuals were homozygous for the wildtype allele. Defects in mRNA splicing were investigated by the detection of illegitimate transcription of the PTH gene in lymphoblastoid cells. The mutation resulted in exon skipping with loss of exon 2, which encodes the initiation codon and the signal peptide, thereby causing parathyroid hormone deficiency.
In a patient with neonatal hypocalcemic seizures (FIH1; 146200), whose parents were consanguineous, Sunthornthepvarakul et al. (1999) identified a T-to-C transition in exon 2 of the PTH gene, resulting in a ser23-to-pro (S23P) substitution in the 25-amino acid prepro-PTH signal peptide. Serum calcium was 1.5 mmol/L (normal, 2.0-2.5); phosphate was 3.6 mmol/L (normal, 0.9-1.5). A few years later, 2 younger sisters and her niece presented with neonatal hypocalcemic seizures. Their intact PTH levels were undetectable during severe hypocalcemia. Genomic DNA from the proposita was sequenced in all exons of the prepro-PTH gene. Genotyping of family members was carried out by identification of a new MspI site created by the mutation. Only affected family members were homozygous for the mutant allele, whereas the parents were heterozygous, supporting autosomal recessive inheritance. As this mutation is at the -3 position in the signal peptide of the prepro-PTH gene, the authors hypothesized that the prepro-PTH mutant might not be cleaved by signal peptidase at the normal position, and it might be degraded in rough endoplasmic reticulum.
In the parathyroid adenoma (see 145000) of a 59-year-old woman with hypercalcemia but undetectable serum PTH levels, in which microarray analysis showed upregulated PTH expression despite negative immunohistochemistry for PTH, Au et al. (2008) identified a 247C-T transition in the PTH gene, resulting in an arg83-to-ter (R83X) substitution and predicting premature termination after 52 amino acids in the secreted PTH peptide. No wildtype sequence was detected in tumor DNA, although analysis of peripheral blood leukocyte DNA revealed heterozygosity for the mutation; loss of heterozygosity analysis showed that the wildtype PTH allele had been deleted in the tumor. The authors confirmed that an N-terminal PTH fragment was produced by tumor cells cultured ex vivo. Noting that Lim et al. (1992) had previously studied the R83X mutation in vitro and demonstrated impairment of translocation across the ER, cleavage of pro-PTH, and secretion of PTH, Au et al. (2008) stated that this case provides evidence that an endogenously produced N-terminal PTH fragment can be biologically active.
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