Alternative titles; symbols
HGNC Approved Gene Symbol: NPPB
Cytogenetic location: 1p36.22 Genomic coordinates (GRCh38): 1:11,857,464-11,858,945 (from NCBI)
Natriuretic peptides comprise a family of 3 structurally related molecules: atrial natriuretic peptide (ANP; 108780), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP; 600296). ANP and BNP act mainly as cardiac hormones, produced primarily by the atrium and ventricle, respectively, while the gene encoding CNP is expressed mainly in the brain. However, other studies demonstrated production of CNP by cultured endothelial cells and by blood vessels in vivo with augmentation of production of CNP by various cytokines and growth factors (Ogawa et al., 1994).
The ANP and BNP genes are tightly linked on human chromosome 1 and mouse chromosome 4 (Steinhelper, 1993; Yang-Feng et al., 1985). Arden et al. (1995) confirmed the assignment to 1p36 by FISH and Southern blot analysis. Pulsed field gel electrophoresis placed ANP and NPPB within 50 kb of each other.
Campbell et al. (2006) found that increased serum levels of soluble VCAM1 (192225) predicted recurrent ischemic stroke (601367) in a study of 252 patients. A smaller but similar trend was noted for serum levels of N-terminal NPPB. Patients in the highest quarters for both sVCAM1 and NT-proBNP levels had 3.6 times the risk of recurrent ischemic stroke compared to patients in the lowest quarters for both biologic markers.
Using microarray analysis, Marchini et al. (2007) showed that human osteosarcoma and chondrosarcoma cell lines carrying an inducible SHOX gene (312865) significantly upregulated NPPB expression upon SHOX induction. Chromatin immunoprecipitation and reporter gene assays confirmed that SHOX bound and activated the NPPB promoter. RT-PCR of human growth plate material showed coexpression of SHOX and NPPB, and immunohistochemical analysis showed that both proteins were expressed in late proliferative, prehypertrophic, and hypertrophic chondrocytes. Marchini et al. (2007) concluded that NPPB is a downstream effector of SHOX in bone.
Mishra and Hoon (2013) showed that the neuropeptide NPPB is expressed in a subset of TRPV1 (602076)-expressing neurons and found that Nppb-null mice selectively lose almost all behavioral responses to itch-inducing agents. Nppb triggered potent scratching when injected intrathecally in wildtype and Nppb-null mice, showing that this neuropeptide evokes itch when released from somatosensory neurons. Itch responses were blocked by toxin-mediated ablation of Nppb receptor-expressing cells, but a second neuropeptide, gastrin-releasing peptide (GRP; 137260), still induced strong responses in the toxin-treated animals. Mishra and Hoon (2013) concluded that their results defined the primary pruriceptive neurons, characterized Nppb as an itch-selective neuropeptide, and revealed the next 2 stages of this dedicated neuronal pathway.
By quantitative trait locus analysis, Devoto et al. (2001) found a possible involvement of chromosomal region 1p36 in the determination of bone mineral density (BMD; see BMND3, 606928). Because the NPPB gene lies within this candidate region and its overexpression results in skeletal overgrowth in transgenic mice, Kajita et al. (2003) analyzed the association between nucleotide variations of the NPPB gene and radial bone mineral density in 378 Japanese postmenopausal women. They found a significant association of the -381T-C variation of the NPPB gene with radial BMD. Homozygous T-allele carriers had the lowest BMD values, homozygous C-allele carriers had the highest, and heterozygous individuals had intermediate radial BMD values, indicating a dosage effect. Accelerated bone loss also correlated with the -381T allele in a 5-year follow-up study. The results suggested that variation of NPPB may be an important determinant of postmenopausal osteoporosis, in part through the mechanism of accelerated postmenopausal bone loss.
Longitudinal bone growth is determined by the process of endochondral ossification in the cartilaginous growth plate, which is located at both ends of vertebrae and long bones and involves many systemic hormones and local regulators. ANP and BNP, as noted earlier, are cardiac hormones that are produced predominantly by the atrium and ventricle, respectively. C-type natriuretic peptide occurs in a wide variety of tissues, where it acts as a local regulator. These peptides can influence body fluid homeostasis and blood pressure control through the activation of 2 guanylyl cyclase-coupled natriuretic peptide receptor subtypes--GC-A and GC-B. Suda et al. (1998) reported marked skeletal overgrowth in transgenic mice that overexpress BNP. Transgenic mice with elevated plasma BNP concentrations exhibited deformed bony skeletons characterized by kyphosis, elongated limbs and paws, and crooked tails. Bone abnormalities resulted from a high turnover of endochondral ossification accompanied by overgrowth of the growth plate. Studies using an in vitro organ culture of embryonic mouse tibias revealed that BNP increases the height of cartilaginous primordium directly, thereby stimulating the total longitudinal bone growth. Thus, an unexpected effect of a natriuretic peptide was demonstrated. No skeletal defects had been reported in transgenic mice overexpressing ANP. Plasma BNP concentrations were markedly elevated in patients with congestive heart failure, to ranges comparable to those in BNP-transgenic mice. Skeletal overgrowth may be exaggerated in BNP-transgenic mice because growth plates remain open for a long time in rodents. An association has been described between congenital heart diseases and scoliosis (Jordan et al., 1972; Reckles et al., 1975). Suda et al. (1998) speculated that overproduction of BNP and/or ANP by the heart might increase bone growth in patients with congenital heart defects, while growth plates are open.
To investigate the precise functional significance of BNP, Tamura et al. (2000) generated mice with targeted disruption of BNP, i.e., Nppb-null mice. They observed multifocal fibrotic lesions in the ventricles of the Nppb-null mice. No signs of systemic hypertension or ventricular hypertrophy were noted. In response to ventricular pressure overload, focal fibrotic lesions increased in size and number in the Nppb-null mice, whereas no focal fibrotic lesions were found in wildtype littermates. This study established BNP as a cardiomyocyte-derived antifibrotic factor in vivo and provided evidence for its role as a local regulator of ventricular remodeling.
Arden, K. C., Viars, C. S., Weiss, S., Argentin, S., Nemer, M. Localization of the human B-type natriuretic peptide precursor (NPPB) gene to chromosome 1p36. Genomics 26: 385-389, 1995. [PubMed: 7601467] [Full Text: https://doi.org/10.1016/0888-7543(95)80225-b]
Campbell, D. J., Woodward, M., Chalmers, J. P., Colman, S. A., Jenkins, A. J., Kemp, B. E., Neal, B. C., Patel, A., MacMahon, S. W. Soluble vascular cell adhesion molecule 1 and N-terminal pro-B-type natriuretic peptide in predicting ischemic stroke in patients with cerebrovascular disease. Arch. Neurol. 63: 60-65, 2006. [PubMed: 16286536] [Full Text: https://doi.org/10.1001/archneur.63.1.noc50221]
Devoto, M., Specchia, C., Li, H.-H., Caminis, J., Tenenhouse, A., Rodriguez, H., Spotila, L. D. Variance component linkage analysis indicates a QTL for femoral neck bone mineral density on chromosome 1p36. Hum. Molec. Genet. 10: 2447-2452, 2001. [PubMed: 11689491] [Full Text: https://doi.org/10.1093/hmg/10.21.2447]
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Kajita, M., Ezura, Y., Iwasaki, H., Ishida, R., Yoshida, H., Kodaira, M., Suzuki, T., Hosoi, T., Inoue, S., Shiraki, M., Orimo, H., Emi, M. Association of the -381T/C promoter variation of the brain natriuretic peptide gene with low bone-mineral density and rapid postmenopausal bone loss. J. Hum. Genet. 48: 77-81, 2003. [PubMed: 12601551] [Full Text: https://doi.org/10.1007/s100380300010]
Marchini, A., Hacker, B., Marttila, T., Hesse, V., Emons, J., Weiss, B., Karperien, M., Rappold, G. BNP is a transcriptional target of the short stature homeobox gene SHOX. Hum. Molec. Genet. 16: 3081-3087, 2007. [PubMed: 17881654] [Full Text: https://doi.org/10.1093/hmg/ddm266]
Mishra, S. K., Hoon, M. A. The cells and circuitry for itch responses in mice. Science 340: 968-971, 2013. [PubMed: 23704570] [Full Text: https://doi.org/10.1126/science.1233765]
Ogawa, Y., Itoh, H., Yoshitake, Y., Inoue, M., Yoshimasa, T., Serikawa, T., Nakao, K. Molecular cloning and chromosomal assignment of the mouse C-type natriuretic peptide (CNP) gene (Nppc): comparison with the human CNP gene (NPPC). Genomics 24: 383-387, 1994. [PubMed: 7698765] [Full Text: https://doi.org/10.1006/geno.1994.1633]
Reckles, L. N., Peterson, H. A., Weidman, W. H., Bianco, A. J., Jr. The association of scoliosis and congenital heart disease. J. Bone Joint Surg. Am. 57: 449-455, 1975. [PubMed: 1141253]
Steinhelper, M. E. Structure, expression, and genomic mapping of the mouse natriuretic peptide type-B gene. Circ. Res. 72: 984-992, 1993. [PubMed: 8097440] [Full Text: https://doi.org/10.1161/01.res.72.5.984]
Suda, M., Ogawa, Y., Tanaka, K., Tamura, N., Yasoda, A., Takigawa, T., Uehira, M., Nishimoto, H., Itoh, H., Saito, Y., Shiota, K., Nakao, K. Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide. Proc. Nat. Acad. Sci. 95: 2337-2342, 1998. [PubMed: 9482886] [Full Text: https://doi.org/10.1073/pnas.95.5.2337]
Tamura, N., Ogawa, Y., Chusho, H., Nakamura, K., Nakao, K., Suda, M., Kasahara, M., Hashimoto, R., Katsuura, G., Mukoyama, M., Itoh, H., Saito, Y., Tanaka, I., Otani, H., Katsuki, M., Nakao, K. Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc. Nat. Acad. Sci. 97: 4239-4244, 2000. [PubMed: 10737768] [Full Text: https://doi.org/10.1073/pnas.070371497]
Yang-Feng, T. L., Floyd-Smith, G., Nemer, M., Drouin, J., Francke, U. The pronatriodilatin gene is located on the distal short arm of human chromosome 1 and on mouse chromosome 4. Am. J. Hum. Genet. 37: 1117-1128, 1985. [PubMed: 2934979]