Alternative titles; symbols
HGNC Approved Gene Symbol: NPPC
Cytogenetic location: 2q37.1 Genomic coordinates (GRCh38): 2:231,921,809-231,926,396 (from NCBI)
Natriuretic peptides comprise a family of 3 structurally related molecules: atrial natriuretic peptide (ANP; 108780), brain natriuretic peptide (BNP; 600295), and C-type natriuretic peptide, CNP, encoded by a gene symbolized NPPC. These peptides possess potent natriuretic, diuretic, and vasodilating activities and are implicated in body fluid homeostasis and blood pressure control.
CNP, which has 22 amino acid residues, was originally isolated from porcine brain (Sudoh et al., 1990). Subsequently, an N-terminally elongated form with 53 amino acid residues was isolated from porcine brain (Minamino et al., 1990). ANP, BNP, and CNP are highly homologous within the 17-residue ring structure formed by an intramolecular disulfide linkage. ANP and BNP act mainly as cardiac hormones, produced primarily by the atrium and ventricle, respectively. CNP was thought to be 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).
Zhang et al. (2010) showed that mural granulosa cells, which line the follicle wall, express Nppc mRNA, whereas cumulus cells surrounding oocytes express mRNA of the Nppc receptor Npr2 (108961), a guanylyl cyclase. Nppc increased cGMP levels in cumulus cells and oocytes and inhibited meiotic resumption in vitro. Meiotic arrest was not sustained in most Graafian follicles of Nppc or Npr2 mutant mice, and meiosis resumed precociously. Oocyte-derived paracrine factors promoted cumulus cell expression of Npr2 mRNA. Therefore, Zhang et al. (2010) concluded that the granulosa cell ligand NPPC and its receptor NPR2 in cumulus cells prevent precocious meiotic maturation and are therefore critical for maturation and ovulation synchrony and for normal female fertility.
On the basis of PCR-analyzed microsatellite length polymorphisms among recombinant inbred strains of mice, Ogawa et al. (1994) found that the Nppc gene is located on mouse chromosome 1. Using somatic hybrid cell methodology, Ogawa et al. (1994) assigned the human NPPC gene to chromosome 2. Extrapolating from studies of homology of synteny, they suggested that NPPC may lie in the 2q24-qter region.
He et al. (2001) reported the hormone-binding thermodynamics and crystal structures at 2.9 and 2.0 angstroms, respectively, of the extracellular domain of the unliganded human NP receptor (NPR-C; 108962) and its complex with CNP, a 22-amino acid natriuretic peptide. A single CNP molecule is bound in the interface of an NPR-C dimer, resulting in asymmetric interactions between the hormone and the symmetrically related receptors.
Associations Pending Confirmation
Hisado-Oliva et al. (2018) screened 668 patients, including 357 with disproportionate short stature and 311 with autosomal dominant idiopathic short stature (ISS), and 29 additional ISS families in an ongoing whole-exome sequencing study, for mutations in the NPPC gene. Mutations in SHOX and NPR2 had previously been excluded. Two heterozygous mutations (R117G and G119C), located in the highly conserved CNP ring, were identified in a Spanish and a Brazilian family, respectively, and were confirmed by Sanger sequencing. Neither variant was present in the 1000 Genomes Project or ExAC databases. In cotransfection experiments in COS-7 cells, both mutants showed a significant reduction in CNP-dependent cGMP synthesis in heterozygous state. The authors noted that the R117G mutation had previously been linked to skeletal abnormalities in the spontaneous Nppc mouse long-bone abnormality (lbab) mutant (Jiao et al., 2007). Because members with and those without the mutations in both families were short, the effect of the mutations on an average-stature person was uncertain. All affected individuals had normal arm span to height ratios. Affected individuals had small hands.
For a discussion of a possible association between variation in the NPPC gene and stature, see STQTL21 (613440).
Chusho et al. (2001) investigated the physiologic significance of CNP in vivo by generating mice with targeted disruption of the gene (Nppc -/- mice). Homozygous null mice showed severe dwarfism as a result of impaired endochondral ossification. They were all viable perinatally, but less than half survived during postnatal development. The skeletal phenotypes were histologically similar to those seen in patients with achondroplasia (100800). Targeted expression of CNP in the growth plate chondrocytes rescued the skeletal defect of Nppc -/- mice and allowed their prolonged survival. This study demonstrated that CNP acts locally as a positive regulator of endochondral ossification in vivo and suggested its pathophysiologic and therapeutic implication in some forms of skeletal dysplasia.
Achondroplasia is the most common genetic form of human dwarfism. CNP regulates endochondral bone growth through guanylyl cyclase-B (GC-B). Although the natriuretic peptide system has been implicated mainly in regulating the cardiovascular system, Suda et al. (1998), Yasoda et al. (1998), and others showed that the CNP/GC-B system is an important regulator of endochondral bone growth. Yasoda et al. (2004) developed transgenic mice, referred to as Nppc mice, with targeted overexpression of CNP in growth-plate cartilage using a transgene containing Col2a1 (120140), a cartilage-specific promoter, and Nppc, the gene encoding CNP. Using a mouse model of achondroplasia with activated fibroblast growth factor receptor-3 (FGFR3; 134934) in cartilage, they generated and analyzed doubly transgenic mice that overexpressed CNP in achondroplastic growth-plate chondrocytes. They showed that the targeted overexpression of CNP in chondrocytes counteracted dwarfism in this mouse model. CNP prevented the shortening of achondroplastic bones by correcting the decreased extracellular matrix synthesis in the growth plate through inhibition of the MAPK pathway of FGF signaling. CNP had no effect on the STAT1 (600555) pathway of FGF signaling that mediates the decreased proliferation and the delayed differentiation of achondroplastic chondrocytes. The results suggested that activation of the CNP/GC-B system in endochondral bone formation may be a new therapeutic strategy for human achondroplasia.
Chusho, H., Tamura, N., Ogawa, Y., Yasoda, A., Suda, M., Miyazawa, T., Nakamura, K., Nakao, K., Kurihara, T., Komatsu, Y., Itoh, H., Tanaka, K., Saito, Y., Katsuki, M., Nakao, K. Dwarfism and early death in mice lacking C-type natriuretic peptide. Proc. Nat. Acad. Sci. 98: 4016-4021, 2001. [PubMed: 11259675] [Full Text: https://doi.org/10.1073/pnas.071389098]
He, X., Chow, D., Martick, M. M., Garcia, K. C. Allosteric activation of a spring-loaded natriuretic peptide receptor dimer by hormone. Science 293: 1657-1662, 2001. [PubMed: 11533490] [Full Text: https://doi.org/10.1126/science.1062246]
Hisado-Oliva, A., Ruzafa-Martin, A., Sentchordi, L., Funari, M. F. A., Bezanilla-Lopez, C., Alonso-Bernaldez, M., Barraza-Garcia, J., Rodriguez-Zabala, M., Lerario, A. M., Benito-Sanz, S., Aza-Carmona, M., Campos-Barros, A., Jorge, A. A. L., Heath, K. E. Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature. Genet. Med. 20: 91-97, 2018. [PubMed: 28661490] [Full Text: https://doi.org/10.1038/gim.2017.66]
Jiao, Y., Yan, J., Jiao, F., Yang, H., Donahue, L. R., Li, X., Roe, B. A., Stuart, J., Gu, W. A single nucleotide mutation in Nppc is associated with a long bone abnormality in lbab mice. BMC Genet. 8: 16, 2007. Note: Electronic Article. [PubMed: 17439653] [Full Text: https://doi.org/10.1186/1471-2156-8-16]
Minamino, N., Kangawa, K., Matsuo, H. N-terminally extended form of C-type natriuretic peptide (CNP-53) identified in porcine brain. Biochem. Biophys. Res. Commun. 170: 973-979, 1990. [PubMed: 2383278] [Full Text: https://doi.org/10.1016/0006-291x(90)92187-5]
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]
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]
Sudoh, T., Minamino, N., Kangawa, K., Matsuo, H. C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain. Biochem. Biophys. Res. Commun. 168: 863-870, 1990. [PubMed: 2139780] [Full Text: https://doi.org/10.1016/0006-291x(90)92401-k]
Yasoda, A., Komatsu, Y., Chusho, H., Miyazawa, T., Ozasa, A., Miura, M., Kurihara, T., Rogi, T., Tanaka, S., Suda, M., Tamura, N., Ogawa, Y., Nakao, K. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nature Med. 10: 80-86, 2004. [PubMed: 14702637] [Full Text: https://doi.org/10.1038/nm971]
Yasoda, A., Ogawa, Y., Suda, M., Tamura, N., Mori, K., Sakuma, Y., Chusho, H., Shiota, K., Tanaka, K., Nakao, K. Natriuretic peptide regulation of endochondral ossification. Evidence for possible roles of the C-type natriuretic peptide/guanylyl cyclase-B pathway. J. Biol. Chem. 273: 11695-11700, 1998. [PubMed: 9565590] [Full Text: https://doi.org/10.1074/jbc.273.19.11695]
Zhang, M., Su, Y.-Q., Sugiura, K., Xia, G., Eppig, J. J. Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes. Science 330: 366-369, 2010. [PubMed: 20947764] [Full Text: https://doi.org/10.1126/science.1193573]