Alternative titles; symbols
HGNC Approved Gene Symbol: NPR3
Cytogenetic location: 5p13.3 Genomic coordinates (GRCh38): 5:32,690,872-32,791,720 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.3 | Boudin-Mortier syndrome | 619543 | Autosomal recessive | 3 |
The family of natriuretic peptides (see 108780) elicit a number of vascular, renal, and endocrine effects that are important in the maintenance of blood pressure and extracellular fluid volume. These effects are mediated by specific binding of the peptides to cell surface receptors in the vasculature, kidney, adrenal, and brain.
Using a bovine ANP C-type receptor cDNA as a hybridization probe, Porter et al. (1990) cloned cDNA encoding the human atrial natriuretic peptide clearance receptor (ANPRC; gene symbol = NPR3) from human placental and kidney cDNA libraries. The ANPC receptor mediates the internalization and metabolic clearance of ANP. The human sequence was shown to be highly homologous to the bovine sequence. Corresponding mRNA was expressed in human placenta, adult and fetal kidney, and fetal heart. Lowe et al. (1990) reported the sequence of the cDNA.
Lowe et al. (1990) assigned the ANPRC gene to chromosome 5 by use of human-specific PCR primers identified by screening a human primer panel on parental DNA samples (shotgun primer screening). The gene was regionalized to 5p14-p13 by in situ hybridization.
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) and its complex with CNP (600296), 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.
In 4 children from 3 unrelated families with Boudin-Mortier syndrome (BOMOS; 619543), characterized by tall stature and elongated digits of the hands and feet with multiple extra epiphyses, who were negative for mutation in the FBN1 gene (134797), Boudin et al. (2018) identified compound heterozygosity or homozygosity for mutations in the NPR3 gene (108962.0001-108962.0004). The mutations segregated fully with disease in each family, and were either not found or were reported at very low frequencies in public variant databases, only in heterozygous state. Functional analysis indicated that all were loss-of-function variants.
It is thought that atrial natriuretic peptide released from the heart in response to atrial stretch binds to a guanylyl cyclase-coupled receptor, which Lopez et al. (1995) symbolized GC-A, in the kidney to mediate natriuresis and diuresis, and to the same receptor in the vasculature to mediate relaxation. Lopez et al. (1995) reported that disruption of the GC-A gene by transfection of mouse embryonic stem cells resulted in mice with chronic elevations of blood pressure on a normal salt diet. Pressure was elevated by 27.4 mm Hg in homozygotes and 10.5 mm Hg in heterozygotes. Unexpectedly, the blood pressure remained elevated and unchanged in response to either minimal salt diet or high salt diet. Aldosterone and ANP concentrations were not affected by the genotype. Thus, the authors speculated that mutations in the receptor gene could explain some salt-resistant forms of essential hypertension in humans. Coupled with other work, this also suggested that the GC-A signaling pathway dominates at the level of peripheral resistance, where it can operate independently of ANP.
In 1979, a mutation designated 'longjohn' (lgj), because affected mice displayed an exceptionally long body, arose in BALB/cJ mice at the Jackson Laboratory. A second allele, designated 'strigosus' (stri), which in Latin means 'long and emaciated,' was identified at the Institut Pasteur; it arose in 1989 in an outbred stock after chemical mutagenesis with ethylnitrosourea. The first and a third allele discovered at the Jackson Laboratory were spontaneous mutations. All 3 mutations were proven to be allelic by progeny testing. The phenotype was found to be recessive and to map to the proximal region of mouse chromosome 15. Analysis of skeletal preparations of stri/stri mice indicated that the endochondral ossification process was slightly delayed, resulting in an extended proliferation zone. Suda et al. (1998) found that transgenic mice overexpressing brain natriuretic peptide exhibited a skeletal overgrowth phenotype. The Npr3 gene mapped in the vicinity of the mouse mutations and thus was considered a candidate gene. Jaubert et al. (1999) reported that all 3 mutations involved the Npr3 gene, and they provided evidence in vivo that there is a natriuretic-related bone pathway, underscoring the importance of natriuretic peptide clearance by NPR3. The NPR3 gene therefore became a candidate for overgrowth syndromes in the human.
In 2 Dutch brothers (family 1) with Boudin-Mortier syndrome (BOMOS; 619543), originally described by de Jong et al. (2014), Boudin et al. (2018) identified compound heterozygosity for mutations in the NPR3 gene: a c.442T-C transition (c.442T-C, NM_001204375.1) in exon 1, resulting in a ser148-to-pro (S148P) substitution within the extracellular domain, and a 1-bp deletion (c.1524delC) in exon 8, resulting in an immediate termination codon (tyr508 to ter, Y508X) within the intracellular domain. Their unaffected parents were each heterozygous for one of the mutations. The missense mutation was not found in the gnomAD database, whereas the 1-bp deletion was present at a very low minor allele frequency (4.83 x 10(-6)). Analysis of transfected HEK293T cells showed retention of the S148P mutant within the cell, with no NPRC receptors on the plasma membrane. Sanger sequencing of cDNA from the affected sibs showed only the S148P variant, indicating that the Y508X variant undergoes nonsense-mediated decay. Biochemical analysis of patient plasma revealed a reduced ratio of N-terminal bioinactive cleavage products to mature active peptide for all ligands, as well as high cGMP levels, suggesting reduced clearance of natriuretic peptides by the defective receptor with consequent increased activity of the NPRA (NPR1; 108960) and NPRB (NPR2; 108961) receptors.
For discussion of the 1-bp deletion (c.1524delC, NM_001204375.1) in exon 8 of the NPR3 gene, resulting in an immediate termination codon (tyr508 to ter, Y508X), that was found in compound heterozygous state in 2 Dutch brothers (family 1) with Boudin-Mortier syndrome (BOMOS; 619543) by Boudin et al. (2018), see 108962.0001.
In a 14-year-old Pakistani boy (family 2) with Boudin-Mortier syndrome (BOMOS; 619543), Boudin et al. (2018) identified homozygosity for a c.1088A-T transversion (c.1088A-T, NM_001204375.1) in exon 4 of the NPR3 gene, resulting in an asp363-to-val (D363V) substitution within the extracellular domain. His unaffected consanguineous parents were heterozygous for the mutation, which was not found in the gnomAD database. Analysis of transfected HEK293T cells showed retention of the D363V mutant within the cell, with no NPRC receptors on the plasma membrane. Biochemical analysis of patient plasma revealed a reduced ratio of N-terminal bioinactive cleavage products to mature active peptide for all ligands, as well as high cGMP levels, suggesting reduced clearance of natriuretic peptides by the defective receptor with consequent increased activity of the NPRA (NPR1; 108960) and NPRB (NPR2; 108961) receptors.
In an 8-year-old girl (family 3) with Boudin-Mortier syndrome (BOMOS; 619543), Boudin et al. (2018) identified homozygosity for a 1-bp deletion (c.248delT, NM_001204375.1) in exon 1 of the NPR3 gene, causing a frameshift predicted to result in a premature termination codon (Val83GlyfsTer105). Her consanguineous unaffected parents were each heterozygous for the mutation, which was not found in the gnomAD database.
Boudin, E., de Jong, T. R., Prickett, T. C. R., Lapauw, B., Toye, K., Van Hoof, V., Luyckx, I., Verstraeten, A., Heymans, H. S. A., Dulfer, E., Van Laer, L., Berry, I. R., Dobbie, A., Blair, E., Loeys, B., Espiner, E. A., Wit, J. M., Van Hul, W., Houpt, P., Mortier, G. R. Bi-allelic loss-of-function mutations in the NPR-C receptor result in enhanced growth and connective tissue abnormalities. Am. J. Hum. Genet. 103: 288-295, 2018. [PubMed: 30032985] [Full Text: https://doi.org/10.1016/j.ajhg.2018.06.007]
de Jong, T. R., Melenhorst, W. B. W. H., Houpt, P. Complete pseudoepiphyses with associated enhanced growth in hands and feet: a report of 2 siblings--case report. J. Hand Surg. Am. 39: 488-492, 2014. [PubMed: 24559625] [Full Text: https://doi.org/10.1016/j.jhsa.2013.12.024]
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]
Jaubert, J., Jaubert, F., Martin, N., Washburn, L. L., Lee, B. K., Eicher, E. M., Guenet, J.-L. Three new allelic mouse mutations that cause skeletal overgrowth involve the natriuretic peptide receptor C gene (Npr3). Proc. Nat. Acad. Sci. 96: 10278-10283, 1999. [PubMed: 10468599] [Full Text: https://doi.org/10.1073/pnas.96.18.10278]
Lopez, M. J., Wong, S. K.-F., Kishimoto, I., Dubois, S., Mach, V., Friesen, J., Garbers, D. L., Beuve, A. Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Nature 378: 65-68, 1995. [PubMed: 7477288] [Full Text: https://doi.org/10.1038/378065a0]
Lowe, D. G., Camerato, T. R., Goeddel, D. V. cDNA sequence of the human atrial natriuretic peptide clearance receptor. Nucleic Acids Res. 18: 3412 only, 1990. [PubMed: 2162522] [Full Text: https://doi.org/10.1093/nar/18.11.3412]
Lowe, D. G., Klisak, I., Sparkes, R. S., Mohandas, T., Goeddel, D. V. Chromosomal distribution of three members of the human natriuretic peptide receptor/guanylyl cyclase gene family. Genomics 8: 304-312, 1990. [PubMed: 1979052] [Full Text: https://doi.org/10.1016/0888-7543(90)90286-4]
Porter, J. G., Arfsten, A., Fuller, F., Miller, J. A., Gregory, L. C., Lewicki, J. A. Isolation and functional expression of the human atrial natriuretic peptide clearance receptor cDNA. Biochem. Biophys. Res. Commun. 171: 796-803, 1990. [PubMed: 2169733] [Full Text: https://doi.org/10.1016/0006-291x(90)91216-f]
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]