Alternative titles; symbols
HGNC Approved Gene Symbol: PTH2R
Cytogenetic location: 2q34 Genomic coordinates (GRCh38): 2:208,359,692-208,494,506 (from NCBI)
Usdin et al. (1995) identified a 7-transmembrane-domain G protein-coupled receptor that selectively recognizes parathyroid hormone (PTH; 168450). The receptor, which they designated PTHR2, is a member of the secretin receptor family of G protein-coupled receptors (see 182098). There is 30 to 70% amino acid sequence identity between receptors within the secretin receptor family, but these receptors have essentially no sequence identity with most known G protein-coupled receptors of the rhodopsin family (see 180380) or with the metabotropic glutamate receptor family (see 601115). PTHR2 is most similar (51% overall amino acid identity) to the PTH/PTHRP receptor (168468). The PTHR2 gene was most abundantly expressed in brain, pancreas, testis, and placenta.
Although both PTH and PTH-related peptide (PTHRP; 168470) bind to the PTH/PTHRP receptor and stimulate cAMP accumulation with similar efficacy, only PTH activates PTHR2. To determine the structural basis for this selectivity, Clark et al. (1998) analyzed receptor chimeras in which the amino terminus and third extracellular domains of the 2 receptors were interchanged. Simultaneous interchange of wildtype amino termini and third extracellular loops eliminated agonist activation but not binding for both receptors. These results suggested that the amino terminus and third extracellular loop of the PTH2 and PTH/PTHRP receptors interact similarly with PTH, and that both domains contribute to differential interaction with PTHRP.
By FISH analysis, Usdin et al. (1996) mapped the PTHR2 gene to chromosome 2q33.
In a 15-month-old boy with nonsyndromic sagittal and metopic craniosynostosis (see 123100), Kim et al. (2015) identified a complex paracentric inversion involving chromosome 2q14.3 and 2q34; whole genome sequencing demonstrated an intronic break of the PTH2R gene, and fluorescence in situ hybridization analysis confirmed disruption of PTH2R.
Meulenbelt et al. (2006) performed linkage analysis in 6 multigenerational families with early-onset osteoarthritis and found significant linkage on chromosome 2q33.3 with a maximum 2-point lod score of 6.05 at marker D2S155 (theta = 0.0). Haplotype analysis of affected family members defined a minimum candidate gene region of 4.6 Mb between D2S1384 and D2S2178, which includes the PTHR2 gene. Meulenbelt et al. (2006) identified a missense variant in PTHR2 that cosegregated with disease in 1 family, but stated that it was unlikely to be the major disease gene for the observed linkage to the osteoarthritis phenotype.
Clark, J. A., Bonner, T. I., Kim, A. S., Usdin, T. B. Multiple regions of ligand discrimination revealed by analysis of chimeric parathyroid hormone 2 (PTH2) and PTH/PTH-related peptide (PTHrP) receptors. Molec. Endocr. 12: 193-206, 1998. [PubMed: 9482662] [Full Text: https://doi.org/10.1210/mend.12.2.0063]
Kim, J., Won, H.-H., Kim, Y., Choi, J. R., Yu, N., Lee, K.-A. Breakpoint mapping by whole genome sequencing identifies PTH2R gene disruption in a patient with midline craniosynostosis and a de novo balanced chromosomal rearrangement. J. Med. Genet. 52: 706-709, 2015. [PubMed: 26044810] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103001]
Meulenbelt, I., Min, J. L., van Duijn, C. M., Kloppenburg, M., Breedveld, F. C., Slagboom, P. E. Strong linkage on 2q33.3 to familial early-onset generalized osteoarthritis and a consideration of two positional candidate genes. Europ. J. Hum. Genet. 14: 1280-1287, 2006. [PubMed: 16912703] [Full Text: https://doi.org/10.1038/sj.ejhg.5201704]
Usdin, T. B., Gruber, C., Bonner, T. I. Identification and functional expression of a receptor selectively recognizing parathyroid hormone, the PTH2 receptor. J. Biol. Chem. 270: 15455-15458, 1995. [PubMed: 7797535] [Full Text: https://doi.org/10.1074/jbc.270.26.15455]
Usdin, T. B., Modi, W., Bonner, T. I. Assignment of the human PTH2 receptor gene (PTHR2) to chromosome 2q33 by fluorescence in situ hybridization. Genomics 37: 140-141, 1996. [PubMed: 8921382] [Full Text: https://doi.org/10.1006/geno.1996.0532]