Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: CALCA
Cytogenetic location: 11p15.2 Genomic coordinates (GRCh38): 11:14,966,668-14,972,351 (from NCBI)
Calcitonin is a peptide hormone synthesized by the parafollicular cells of the thyroid. It causes reduction in serum calcium, an effect opposite to that of parathyroid hormone (PTH; 168450).
Dayhoff (1972) reported that human calcitonin contains 32 amino acids and has a molecular mass of 3.4 kD. Using recombinant DNA techniques to analyze the calcitonin mRNA, Jacobs et al. (1981) found that calcitonin is flanked at both its amino and carboxyl termini by peptide extension linked to the hormone by short sequences of basic amino acids. The authors concluded that multiple calcitonin polypeptides are encoded in a single messenger RNA. Rosenfeld et al. (1982) presented evidence that alternative RNA splicing of the transcripts of the calcitonin gene is responsible for the production of different polypeptide products. Genomic mapping results were consistent with the existence of a single calcitonin gene.
Rosenfeld et al. (1983) showed that alternative processing of the RNA transcribed from the calcitonin gene results in the production of an mRNA in neural tissue distinct from that in thyroidal 'C' cells. The novel neuropeptide was referred to as calcitonin gene-related peptide (CGRP).
Amara et al. (1982) noted that the calcitonin mRNA predominates in the thyroid, while the CGRP-specific mRNA appears to predominate in the hypothalamus. The authors proposed that developmental regulation of RNA processing is used to increase the diversity of neuroendocrine gene expression.
By sequencing CT and CGRP cDNA, Nelkin et al. (1984) determined that their 5-prime sequences are identical. Like the rat calcitonin gene, the domain arrangement of the human calcitonin gene is 5-prime--common region--CT--CGRP--3-prime. Both transcripts were detected in all 10 human lung tumor cell lines examined, including 6 small cell, 1 large cell, 2 adeno-, and 1 squamous cell carcinoma. All expressed CGRP mRNA, and most also contained detectable CT mRNA.
By RT-PCR of medullary thyroid carcinoma mRNA, Le Moullec et al. (1984) cloned the calcitonin cDNA. The deduced 141-amino acid precursor protein has a calculated molecular mass of 15.5 kD. The precursor contains an N-terminal 84-amino acid cryptic peptide and leader sequence, followed by the 32-amino acid calcitonin sequence and a 25-amino acid C-terminal peptide. SDS-PAGE detected the precursor protein at an apparent molecular mass of 14.5 kD.
Katacalcin (kata-, Greek; down) was the name given by A. P. Waterson to a 21-amino acid peptide that flanks calcitonin on its C-terminal side in the large precursor polyprotein from which calcitonin is cleaved. Concentration of the hormone is higher in males than in females and approximately equimolar with calcitonin; doubles within 5 min of calcium infusion; and is markedly raised in cases of medullary thyroid carcinoma (MTC; 155240). Katacalcin was discovered by use of recombinant DNA technology rather than by traditional techniques of tissue extraction and purification based on biologic assay; like calcitonin, it may be involved in both plasma calcium regulation and skeletal maintenance (Hillyard et al., 1983).
Breimer et al. (1988) reviewed the organization, expression, and splicing of the calcitonin genes and the structure and function of the peptides they encode.
Breimer et al. (1988) determined that the alpha-calcitonin/CGRP gene spans approximately 6.5 kb and contains 6 exons. The first 3 exons are present in both calcitonin and CGRP mRNA, although exon 1 is not translated. Exon 4 contains the calcitonin-coding sequence. Exon 5 encodes the CGRP sequence.
Cryoelectron Microscopy
Liang et al. (2018) reported the structure of the human CGRP receptor, a heterodimer of the calcitonin receptor-like receptor (CALCRL; 114190) and receptor activity-modifying protein-1 (RAMP1; 605153), in complex with CGRP and a Gs-protein heterotrimer at 3.3-angstrom global resolution, determined by cryoelectron microscopy. The RAMP1 transmembrane domain sits at the interface between transmembrane domains 3, 4, and 5 of CALCRL, and stabilizes CALCRL extracellular loop 2. RAMP1 makes only limited direct contact with CGRP, consistent with its function in allosteric modulation of CALCRL. Molecular dynamics simulations indicated that RAMP1 provides stability to the receptor complex, particularly in the positioning of the extracellular domain of CALCRL.
Using somatic cell hybrids, Hoppener et al. (1984) assigned the human calcitonin gene to 11p14-qter. The calcitonin gene was found to contain a polymorphic site for restriction endonuclease TaqI. Przepiorka et al. (1984) mapped the calcitonin gene to 11p by molecular hybridization of a human calcitonin cDNA probe to DNA from human-rodent hybrid cells. In situ hybridization narrowed the assignment to 11p15-p13. In a cell line derived from a particular virulent medullary carcinoma of the thyroid, Testa (1984) found a chromosomal rearrangement affecting 11p. Simpson et al. (1984) assigned the calcitonin gene to chromosome 11 by use of a cDNA clone isolated from medullary thyroid carcinoma and a somatic cell hybrid panel. With a TaqI RFLP detected by this probe, they studied linkage of the calcitonin locus and multiple endocrine neoplasia II (MEN2; 171400); negative lod scores were found at all recombination values.
In 2 tumors with mitotic deletions, Henry et al. (1989) found that CALCA must lie distal to PTH in 11p15.5; in both tumors the CALCA locus was lost and the PTH locus retained. It may be of functional significance that the PTH and calcitonin genes are close together, since they are the yin and the yang of the control of calcium metabolism.
Hoovers et al. (1993) used fluorescence in situ hybridization to prometaphase chromosomes, pulsed field gel electrophoresis analysis, and 2-color in situ hybridization to interphase nuclei to map CALCA, CALCB, and the pseudogene CALC3 to a 220-kb SacII fragment on 11p15.2-p15.1. The related islet amyloid polypeptide (IAPP; 147940) gene was assigned to 12p12.3-p12.1 by the same methods. The results supported the evolutionary relationship between the calcitonin/CGRP genes and the IAPP gene and between parts of human chromosomes 11 and 12.
In the mouse, both Pth and calcitonin are coded by chromosome 7 (Lalley et al., 1987).
Pseudogene
Hoppener et al. (1988) described a calcitonin pseudogene, CALC3, and reviewed information on the CALC genes. The CALC1 gene produces calcitonin (encoded by exon 4) or calcitonin gene-related peptide (encoded by exon 5) in a tissue-specific fashion. The CALC2 gene (CALCB; 114160) produces a second calcitonin gene-related peptide, but probably not a second calcitonin. The presumed pseudogene CALC3 does not seem to encode either peptide. Like the other 2 CALC genes, the CALC3 gene was found to be located on human chromosome 11.
Calcitonin
In patients with medullary thyroid cancer, the clinical course of disease ranges from rapid tumor progression to long-lasting stable disease. Saller et al. (2002) investigated whether circulating tumor cells can be detected in the peripheral blood of patients with MTC by RT-PCR targeted to CT mRNA and whether the results of this method are correlated with disease manifestation and metastatic potential. Blood samples from 19 consecutive patients with MTC and elevated CT levels were analyzed. Four had newly diagnosed MTC, and 15 had undergone total thyroidectomy. Six of 19 patients had detectable CT mRNA by RT-PCR. CT levels in the 6 CT mRNA-positive patients were significantly higher than those in the 13 CT mRNA-negative patients. CT mRNA was detectable in 5 of 8 patients with distant metastases, in 1 of 6 patients with local/regional lymph node metastases, but in none of 2 patients with newly diagnosed, organ-confined MTC or 3 patients with surgically treated MTC without tumor manifestation by various imaging studies. Saller et al. (2002) concluded that they had established an RT-PCR-based procedure that detected circulating CT-producing cells in the peripheral blood of patients with MTC.
Costante et al. (2007) studied the diagnostic accuracy of systematic routine serum calcitonin measurement in nonmultiple endocrine neoplasia type II patients with nodular thyroid disease. The results indicated that CT screening of thyroid nodules is a highly sensitive test for early diagnosis of MTC, but confirmatory stimulation testing is necessary in most cases to identify true positive increases.
Calcitonin Gene-Related Peptide
Rosenfeld et al. (1983) noted that the distribution of CGRP-producing cells and pathways in the brain and other tissues suggests functions for CGRP in nociception, ingestive behavior, and modulation of the autonomic and endocrine systems. CGRP-containing neurons were detected particularly in association with heart and blood vessels. CGRP was shown to have potent vasodilator action and may be an important regulator of vascular tone and blood flow (Tippins, 1986). Tschopp et al. (1985) determined the location of CGRP and its binding sites in the CNS and pituitary. Goltzman and Mitchell (1985) identified discrete receptors for CT and CGRP in the nervous system and in peripheral tissues. Tiller-Borcich et al. (1988) found that CGRP is concentrated in the locus ceruleus in the human. CGRP has very potent hemodynamic activity, and the locus ceruleus is the main source of noradrenergic neurotransmission in the CNS.
Mathe et al. (1994) examined the concentration of calcitonin gene-related peptide immunoreactivity in the CSF of 63 patients with major depression (608516) with that found in the CSF of 28 patients with schizophrenia (181500) and 20 controls. Patients with all forms of major depression had higher levels of CGRP in the spinal fluid than did patients with schizophrenia or controls. The authors suggested that the increased concentration of CGRP may be a marker trait of major depressive disorder.
In patients with migraine headache (see 157300), Goadsby et al. (1990) found a substantial elevation of CGRP in the external jugular vein. In 9 patients with a history of migraine without aura, Lassen et al. (2002) found that intravenous infusion of CGRP resulted in a headache during the following 11 hours, as compared to 1 of 9 patients who received placebo. In 3 patients who had the infusion, the delayed headache fulfilled the International Headache Society criteria for migraine without aura. The authors suggested a causative role for CGRP in migraine headache. Olesen et al. (2004) presented evidence suggesting that a CGRP receptor (CALCRL; 114190) antagonist may be effective in the treatment of a subgroup of patients with migraine. In rats, Levy et al. (2005) found that administration of Cgrp increased dural blood flow but did not activate or sensitize meningeal nociceptors, suggesting that the role of CGRP in migraine does not involve a direct peripheral action on these nociceptors.
Upon venous CGRP infusion, Hansen et al. (2008) found no difference in the incidence of reported migraines or migraine-like headaches between 10 controls and 9 patients with familial hemiplegic migraine (FHM1, 141500; FHM2, 602481). CGRP did not induce aura in any individuals. The findings suggested that FHM patients do not show hypersensitivity to the CGRP pathway, as had been observed in patients with migraine without aura (MO), suggesting that the FHM and MO phenotypes have different pathophysiologic mechanisms.
Carter et al. (2013) identified CGRP-expressing neurons in the outer external lateral subdivision of the parabrachial nucleus that project to the laterocapsular division of the central nucleus of the amygdala as forming a functionally important circuit for suppressing appetite. Using genetically encoded anatomic, optogenetic, and pharmacogenetic tools, Carter et al. (2013) demonstrated that activation of these neurons projecting to the central nucleus of the amygdala suppresses appetite. In contrast, inhibition of these neurons increases food intake in circumstances when mice do not normally eat and prevents starvation in adult mice whose agouti-related peptide neurons are ablated.
Using monocyte-derived Langerhans cells (LCs) and a macrophage-tropic (see CCR5, 601373) human immunodeficiency virus (HIV)-1 (see 609423) molecular clone, Ganor et al. (2013) showed that CGRP acted via CRLR (CALCRL) expressed on LCs and interfered with multiple steps of LC-mediated HIV-1 transmission. CGRP increased langerin (CD207; 604862) expression while decreasing that of selected integrins, such as CD1A (188370), CD11C (ITGAX; 151510), and DCSIGN (CD209; 604672). CGRP also activated NFKB (see 164011), resulting in decreased intracellular HIV-1, limited LC-T cell conjugate formation, and elevated secretion of the CCR5-binding chemokine CCL3 (182283). These mechanisms efficiently inhibited HIV-1 transfer from LCs to T cells. Compared with healthy humans and macaques, HIV-1 infection resulted in decreased plasma CGRP levels that could be reversed by highly active antiretroviral treatment. Ganor et al. (2013) concluded that CGRP acts at molecular and cellular levels to limit mucosal HIV-1 transmission and that CRLR agonists may have therapeutic potential.
Breimer et al. (1988) noted that the organization of the CALCB gene (114160) is similar to that of the alpha gene, and it is likely that the 2 arose by duplication. There is no evidence for the production of calcitonin mRNA from the beta gene. Perhaps the beta gene allows the expression of CGRP at sites or in circumstances where the inadvertent production of calcitonin could be deleterious.
This variant, formerly titled OSTEOPOROSIS, has been reclassified as a polymorphism based on the retraction of the report by Alevizaki et al. (1989) by Alevizaki and Legon (1989).
In a young male patient with osteoporosis, Alevizaki et al. (1989) identified a 1-bp (T) insertion at position 462 in the intron separating exons 4 and 5 in the calcitonin gene. The patient had no detectable plasma concentrations of calcitonin and had responded well to calcitonin replacement treatment for 9 years, leading the authors to suggest that this was a pathogenic mutation. However, Alevizaki and Legon (1989) later found this sequence to be widespread in the general population and concluded that it is a neutral polymorphism.
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