Alternative titles; symbols
HGNC Approved Gene Symbol: NPR2
SNOMEDCT: 718559000;
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:35,791,591-35,809,731 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p13.3 | Acromesomelic dysplasia 1, Maroteaux type | 602875 | Autosomal recessive | 3 |
| Epiphyseal chondrodysplasia, Miura type | 615923 | Autosomal dominant | 3 | |
| Short stature with nonspecific skeletal abnormalities | 616255 | Autosomal dominant | 3 |
The NPR2 gene encodes a guanylate cyclase that catalyzes the conversion of intracellular guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) (summary by Miura et al., 2014).
In the course of cloning the human ANPA receptor (NPR1; 108960) from a placenta cDNA library, Chang et al. (1989) obtained an NPR2 clone, which they called ANPB receptor. The deduced 1,048-amino acid protein has a 22-amino acid signal peptide, followed by a 442-amino acid extracellular domain, which contains 7 potential N-glycosylation sites and 6 cysteines, a transmembrane domain, an arg-lys stop transfer sequence, and a 569-amino acid cytoplasmic domain, which contains 1 potential N-glycosylation site and 9 cysteines. The mature protein has a calculated molecular mass of approximately 115 kD. The cytoplasmic domain contains both a protein kinase domain and a guanylate cyclase domain. The ANPB receptor shares domain structure and significant amino acid identity with human ANPA receptor and bovine ANPC receptor (NPR3; 108962).
By assaying the membrane fraction of transfected COS-7 cells, Chang et al. (1989) found that expression of the human ANPB receptor increased membrane binding of radiolabeled human alpha-ANP (NPPA; 108780) and bovine brain ANP (NPPB; 600295) and increased production of cyclic GMP compared with controls.
The homodimeric transmembrane receptor natriuretic peptide receptor B produces cytoplasmic cyclic GMP from GTP on binding its extracellular ligand, C-type natriuretic peptide (CNP, NPPC; 600296) (Lincoln and Cornwell, 1993).
Sessions et al. (2009) identified insect host factors required for dengue virus (see 614371) propagation by carrying out a genomewide RNA interference screen in D. melanogaster cells using a well established 22,632 double-stranded RNA library. This screen identified 116 candidate dengue virus host factors (DVHFs). Although some were previously associated with flaviviruses, most of the DVHFs were newly implicated in dengue virus propagation. The dipteran DVHFs had 82 readily recognizable human homologs and, using a targeted short interfering RNA screen, they showed that 42 of these are human DVHFs. These include NPR2, SEC61B (609214), TMEM214, TAZ (300394), EXDL2, and CNOT2 (604909). Sessions et al. (2009) concluded that this overlap indicates notable conservation of required factors between dipteran and human hosts.
Zhang et al. (2010) showed that mural granulosa cells, which line the follicle wall, express natriuretic peptide precursor type C (Nppc) mRNA, whereas cumulus cells surrounding oocytes express mRNA of the Nppc receptor Npr2, 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.
Rehemudula et al. (1999) determined that the NPR2 gene contains 22 coding exons and spans approximately 16.5 kb. The 5-prime flanking region contains 10 potential SP1 (189906)-binding sites, but no TATA box. Intron 2 contains a CA/GT microsatellite repeat.
By PCR analysis of genomic DNA from somatic cell hybrids, Lowe et al. (1990) assigned the ANPRB gene to 9p22-p11. The localization was further narrowed to 9p21-p12 by in situ hybridization.
Acromesomelic Dysplasia 1
Using a positional candidate gene approach, Bartels et al. (2004) identified mutations in the NPR2 gene as the cause of acromesomelic dysplasia-1 (AMD1; 602875), also known as Maroteaux type, an autosomal recessive skeletal dysplasia. Bartels et al. (2004) sequenced DNA from 21 families affected by AMD1 and found 4 nonsense mutations, 4 frameshift mutations, 2 splice site mutations, and 11 missense mutations in the NPR2 gene (see, e.g., 108961.0001-108961.0004). They found that obligate carriers of NPR2 mutations had heights below the mean for matched controls. In a functional assay of 3 missense mutations, they found markedly deficient guanylyl cyclase activity. CNP, the extracellular ligand of NPR2, is implicated in the regulation of skeletal growth in transgenic and knockout mice (Chusho et al., 2001; Yasoda et al., 2004). Since CNP is able to increase chondrocyte proliferation, matrix synthesis, and cell hypertrophy in the growth plate, Bartels et al. (2004) hypothesized that each of these effects is mediated by signaling via NPR2.
Hume et al. (2009) hypothesized that missense mutations of NPRB associated with AMD1 primarily affect NPRB function by the arrest of receptor trafficking at the endoplasmic reticulum (ER) due to conformational change, rather than an impairment of ligand binding, transmission of signal through the membrane, or catalytic activity. Twelve missense mutations found in AMD1 patients and cn/cn mice were generated by site-directed mutagenesis and transiently overexpressed in HeLa cells. Confocal microscopy revealed that 11 of the 12 mutants were retained in the ER. Determination of the ligand-dependent cGMP response confirmed that ER-retained NPRB mutants were nonfunctional. Meanwhile, the only cell surface-targeted NPRB missense mutant (D176E; 108961.0003) displayed greatly reduced enzymatic activity due to impaired ligand binding. The authors concluded that in the majority of cases of AMD1 associated with missense NPRB mutations, disease appears to result from defects in the targeting of the ER receptor to the plasma membrane.
Using rat cDNAs, Dickey et al. (2016) found that AMD1-causing mutations that inhibited initial N-glycosylation of Npr2 in the ER, but not secondary glycosylation of Npr2 in the Golgi, decreased or eliminated CNP-stimulated guanylyl cyclase activity. N-glycosylation of asn24 was particularly important in determining Npr2 activity. Deglycosylation of fully processed wildtype Npr2 did not alter its guanylyl cyclase activity, suggesting that glycosylation is required for proper folding of Npr2, but not directly for its cyclase activity.
Epiphyseal Chondrodysplasia, Miura Type
In 3 Japanese family members with tall stature, macrodactyly of the great toes, and scoliosis (ECDM; 615923), Miura et al. (2012) identified a heterozygous missense mutation in the NPR2 gene (V883M; 108961.0005). Amino acid val883 is located in a highly conserved region of the carboxyl-terminal guanylyl cyclase domain of NPR2. Transfection experiments showed a gain of function of this variant with increased cGMP production, independent of C-type natriuretic peptide in HEK293A transfected cells.
In a patient with tall stature (+5 SD), long fingers, mild scoliosis, and broad but not particularly long halluces, Hannema et al. (2013) identified a heterozygous mutation in the NPR2 gene (R655C; 108961.0006). Ex vivo studies using fibroblasts of this patient as well as transfected HEK293A cells expressing mutant NPR2 showed markedly increased cGMP production, stimulated by C-type natriuretic peptide. Coimmunoprecipitation of FLAG-tagged wildtype NPR2 and Myc-tagged mutant NPR2 confirmed a tight interaction, suggesting an activating effect.
In affected members of a 4-generation Korean kindred with tall stature, macrodactyly of the great toes, scoliosis, and coxa valga with epiphyseal dysplasia, Miura et al. (2014) identified a heterozygous missense mutation in the NPR2 gene (A488P; 108961.0007). Serum NT-proCNP was not overproduced in the proband. An in vitro functional assay indicated that A488P is a gain-of-function mutation. Transfection experiments with HEK293A cells showed equal expression of both wildtype and mutated allele, but only the latter showed production of cGMP in the absence of CNP.
In a mother and her 2 daughters with ECDM, Lauffer et al. (2020) identified heterozygosity for a 6-bp deletion in the NPR2 gene (108961.0014). Molecular modeling suggested that the mutation may affect dimer stability or conformation, resulting in an activated state even in the absence of CNP or in a hyperactivated state by stabilizing the CNP-induced active receptor conformation. Testing in fibroblasts from the mother and in HEK293 cells transfected with the mutant NPR2 demonstrated that basal and CNP-stimulated cGMP levels were increased compared to controls.
Short Stature with Nonspecific Skeletal Abnormalities
Olney et al. (2006) determined the phenotypic features of heterozygous carriers of NPR2 mutations in members of a single large kindred in which the proband had Maroteaux-type acromesomelic dysplasia (AMD1) and a homozygous frameshift mutation in the NPR2 gene (108961.0008). Sixteen family members were NPR2 mutation carriers. Height z-scores of these carriers were -1.8 +/- 1.1 (mean +/- SD), which was significantly less than the 23 noncarrier family members and the general population. However, there was no difference in body proportion between carriers and noncarriers. The authors concluded that heterozygous mutations in NPR2 are associated with short stature (SNSK; 616255). Assuming 1 in 700 persons unknowingly carries an NPR2 mutation, their data suggested that approximately 1 in 30 individuals with idiopathic short stature is a carrier of NPR2 mutations.
Vasques et al. (2013) sequenced the NPR2 gene in 47 unrelated patients with short stature, defined by the authors as postnatal short stature, height -2 SD or less, unremarkable medical history, and absence of abnormal findings on clinical examination or in laboratory tests that could account for short stature. Three probands were found to have heterozygous mutations in the NPR2 gene (108961.0009-108961.0011). Cells transfected with the mutants failed to produce cyclic GMP after treatment with C-type natriuretic peptide (CNP). Cotransfection experiments with wildtype and mutant cDNA also showed significantly decreased cGMP levels when compared to cells cotransfected with wildtype and an empty vector, suggesting a dominant-negative effect.
Amano et al. (2014) screened 101 unrelated Japanese individuals with isolated short stature for mutation in the NPR2 gene and identified heterozygous missense mutations in 2 (108961.0012-108961.0013) Coexpression of each mutant and wildtype led to a significant loss in the CNP-dependent cGMP response compared with that of the empty vector and wildtype, indicating a dominant-negative effect.
By gene targeting, Tamura et al. (2004) generated mice lacking Npr2. Homozygous mutant pups were born at the expected mendelian ratios. Mutant animals exhibited self-clasping and priapism, suggesting neuronal disorders, but no histologic abnormalities were found in the brain and spinal cord of homozygous mutant mice. Npr2 null mice showed an impairment of endochondral ossification and attenuation of longitudinal vertebra or limb-bone growth, resulting in dwarfism that became more prominent as null mice grew older. Male Npr2 null mice were fertile, but female mutants were not, due to failure of the female reproductive tract to develop. Tamura et al. (2004) concluded that NPR2 is critical for the development of both bone and female reproductive organs.
Geister et al. (2013) discovered a spontaneous mutant allele of mouse Npr2 named peewee (pwe) that caused severe disproportionate dwarfism and female infertility. They identified the pwe mutation as a 4-bp deletion in exon 3 of Npr2 that resulted in a frameshift and generation of a premature stop codon within the extracellular ligand-binding domain. Pwe homozygotes exhibited growth delay and disproportionate dwarfism that was evident at 2 weeks of age. The proximal skeletal elements of the appendicular skeleton were the most severely affected in pwe mouse. There was no reduction in the width of the skull or ribs, and the femur did not have a thinner dimension. Growth insufficiency of pwe mutants was indistinguishable from that of Npr2 -/- mice and was caused by reduction in the hypertrophic and proliferative zones of the growth plate. Mineralization of skeletal elements was normal. Female infertility was due to premature oocyte meiotic resumption, and the pituitary and uterus appeared to be normal. Treatment of fetal tibia explants with MAPK (see MAPK1; 176948) inhibitors rescued the pwe growth defect.
In a consanguineous Brazilian family with Maroteaux-type acromesomelic dysplasia (AMD1; 602875), Bartels et al. (2004) described a homozygous 94C-A transversion in the NPR2 cDNA, resulting in a pro32-to-thr (P32T) change in the protein, as the molecular basis of the disorder.
In a consanguineous Turkish family with Maroteaux-type acromesomelic dysplasia (AMD1; 602875), Bartels et al. (2004) found a homozygous 343T-G transversion in the NPR2 cDNA, causing a trp115-to-gly amino acid substitution (W115G), as the basis of the disorder.
In a nonconsanguineous U.S. white family with Maroteaux-type acromesomelic dysplasia (ADM1; 602875), Bartels et al. (2004) found compound heterozygosity for a missense mutation and a premature stop mutation in the NPR2 gene as the basis of the disorder. The allele inherited from the mother carried a 528T-A transversion, resulting in an asp176-to-glu (D176E) change in the protein. The allele inherited from the father carried a 1162C-T transition, resulting in an arg388-to-ter (R388X) substitution (108961.0004). The father was 170 cm tall as compared to the average matched control height of 177 cm; the mother was 150 cm tall as compared with the average matched control of 163.3 cm.
For discussion of the arg388-to-ter (R388X) mutation in the NPR2 gene that was found in compound heterozygous state in affected members of a family with the Maroteaux type of acromesomelic dysplasia (AMD1; 602875) by Bartels et al. (2004), see 108961.0003.
In all 3 affected members of a Japanese family segregating Miura-type epiphyseal chondrodysplasia (ECDM; 615923), Miura et al. (2012) identified a heterozygous c.2647G-A transition in the NPR2 gene, resulting in a val833-to-met (V833M) substitution at a highly conserved residue in the C-terminal guanylyl cyclase domain, which was predicted to cause a gain of function. The mutation was not present in the dbSNP of JSNP databases or in 214 alleles from Japanese controls. Transfection experiments showed a gain of function of this variant with increased cGMP production, independent of C-type natriuretic peptide in HEK293A transfected cells.
Robinson et al. (2013) performed transfection experiments with the NPR2 V833M mutation in HEK293 cells and showed that the variant led to a 20-fold increase in cGMP levels by activating guanylyl cyclase B in the absence of CNP. Enzyme analysis showed that basal activity of V883M guanylyl cyclase B was elevated, with reduced expression levels. Substrate velocity experiments indicated that the V883M mutation increases basal maximal velocity and allows CNP to reduce the Michaelis constant (Km) in the absence of ATP. The authors concluded that this mutation might lead to a structural change that locks the enzyme in a conformation mimicking the ATP-bound state.
Yamamoto et al. (2019) found that transgenic mice expressing human NPRB with the V883M mutation exhibited postnatal skeletal overgrowth due to thickening of the hypertrophic zone in growth plates. The gain-of-function V883M mutation led to phosphorylation of Creb1 (123810) and upregulation of cyclin D1 (CCND1; 168461) in hypertrophic chondrocytes of transgenic mice, resulting in continued proliferation even after cells became hypertrophic.
By exome sequencing in a patient with extremely tall stature (+5 SD) and mild skeletal deformities (ECDM; 615923), Hannema et al. (2013) identified a heterozygous c.1963C-T transition in the NPR2 gene, resulting in an arg655-to-cys (R655C) substitution in the kinase homology domain (KHD). The mutation, which was predicted to result in a gain of function, was not found in the patient's son or sister. Ex vivo studies of the proband's fibroblasts confirmed that the exogenously expressed variant mediated markedly enhanced CNP/cGMP signaling.
In affected members of a Korean kindred with Miura-type epiphyseal chondrodysplasia (ECDM; 615923), Miura et al. (2014) identified a heterozygous c.1462G-C transversion in the NPR2 gene, resulting in an ala488-to-pro (A488P) substitution at a highly conserved residue in the juxtamembranous cytoplasmic domain. This sequence variation eliminates a NheI cleavage site. The mutation, which was confirmed by Sanger sequencing, was not present in unaffected family members, in the dbSNP (build 137) or NHLBI Exome Sequencing Project databases, or in 400 alleles of Korean or Japanese controls. The mutation was predicted to lead to a gain of function. Transfection experiments with HEK293A cells showed equal expression of both wildtype and mutated allele, but only the latter showed production of cGMP in the absence of CNP.
Acromesomelic Dysplasia 1
In a 1-year-old girl with Maroteaux-type acromesomelic dysplasia (AMD1; 602875) from a large 4-generation Caucasian family primarily of Irish descent, Olney et al. (2006) identified homozygosity for a 1-bp deletion in exon 4 of the NPR2 gene (c.1092delT), predicted to cause a frameshift and premature termination (Ile364fsTer376). Loss of NPRB function would result either from nonsense-mediated mRNA decay or from production of a severely truncated receptor that lacks the transmembrane and guanylyl cyclase domains. The parents, who shared a common ancestor, were heterozygous for the mutation.
Short Stature with Nonspecific Skeletal Abnormalities
Olney et al. (2006) noted that in the initial description of NPR2 mutations in patients with Maroteaux-type acromesomelic dysplasia by Bartels et al. (2004), data from adult mutation carriers showed that they were on average 5.7 cm shorter than population-matched controls. Olney et al. (2006) found that the father and mother of the girl they reported with Maroteaux-type AMD and a c.1092delT mutation had short stature (SNSK; 616255), with height z-scores of -2.0 and -3.6, respectively. The authors obtained data on 39 members from 4 generations of the family; 16 were heterozygous carriers of the c.1092delT mutation and 23 were not. The mean height z-score for the carriers was -1.8 +/- 1.1 (mean +/- SD) versus -0.4 +/- -0.8 for the noncarriers (p less than 0.0005). The height z-score of the carriers was also less than the general population (p less than 0.0005).
By direct sequencing of the NPR2 gene in an 11-year-old Brazilian boy with short stature with nonspecific skeletal abnormalities (SNSK; 616255), Vasques et al. (2013) identified a heterozygous c.2455C-T transition, resulting in an arg819-to-cys (R819C) substitution. A skeletal survey in the boy revealed shortened metacarpals. His mother, who also carried the mutation, had short stature and altered body proportions. The mutation was not present in 72 control samples from the same ethnic background with average stature or in the 1000 Genomes database (2,184 alleles). Cells transfected with the R819C mutant failed to produce cyclic GMP after treatment with C-type natriuretic peptide (CNP). Cotransfection with wildtype and mutant cDNA also showed significantly decreased cGMP levels when compared to cells cotransfected with wildtype and an empty vector, suggesting a dominant-negative effect.
By direct sequencing of the NPR2 gene in a 12-year-old Brazilian boy with mild disproportionate short stature with nonspecific skeletal abnormalities (SNSK; 616255), Vasques et al. (2013) identified a heterozygous c.226T-C transition, resulting in a ser76-to-pro (S76P) substitution. The mutation was also identified in his father and older sister, both of whom had mild disproportionate short stature. The mutation, which was confirmed by Sanger sequencing, was not present in 72 control samples from the same ethnic background with average stature or in the 1000 Genomes Project database (2,184 alleles). Cells transfected with the S76P mutant failed to produce cyclic GMP after treatment with C-type natriuretic peptide (CNP). Cotransfection with wildtype and mutant cDNA also showed significantly decreased cGMP levels when compared to cells cotransfected with wildtype and an empty vector, suggesting a dominant-negative effect.
By direct sequencing of the NPR2 gene in a 9-year-old Brazilian boy with short stature with nonspecific skeletal abnormalities (SNSK; 616255), Vasques et al. (2013) identified a heterozygous c.788G-C transversion resulting in an arg263-to-pro (R263P) substitution. The patient had altered body proportions. The mutation, which was confirmed by Sanger sequencing, was also found in his father and his grandfather, both of whom had short stature. The mutation was not present in 72 control samples from the same ethnic background with average stature or in the 1000 Genomes Project database (2,184 alleles). Cells transfected with the R263P mutant failed to produce cyclic GMP after treatment with C-type natriuretic peptide (CNP). Cotransfection with wildtype and mutant cDNA also showed significantly decreased cGMP levels when compared to cells cotransfected with wildtype and an empty vector, suggesting a dominant-negative effect.
By direct sequencing of the NPR2 gene in 101 unrelated Japanese patients with short stature (SNSK; 616255), Amano et al. (2014) identified a heterozygous c.328C-T transition, resulting in an arg110-to-cys (R110C) mutation in 1 proband (adult height -2.8 SD) and his mother (adult height -1.3 SD). The father and 1 sib did not carry the mutation; another sib was not tested. The mutation was not present in the dbSNP or 1000 Genomes Project databases or in 100 Japanese control individuals. Coexpression of the mutant and wildtype led to a significant loss in the CNP-dependent cGMP response compared with that of the empty vector and wildtype, indicating a dominant-negative effect. Western blot analysis showed that the R110C mutant did not exist in the O-glycosylated form and did not show cell surface expression when compared to the Q417E (108961.0013) mutant. The R110C variant colocalized with an endoplasmic reticulum (ER) marker, suggesting that this variant causes defective trafficking from the ER to the Golgi apparatus.
By direct sequencing of the NPR2 gene in 101 unrelated Japanese patients with short stature (SNSK; 616255), Amano et al. (2014) identified a heterozygous c.1249C-G transversion, resulting in a gln417-to-glu (Q417E) substitution in 1 proband (adult height -2.6 SD) and her mother (adult height -2.5 SD). The mutation was not found in 2 sibs of the proband, but her father's DNA was not tested. The mutation was not present in the dbSNP or the 1000 Genomes Project databases or in 100 Japanese control individuals. Coexpression of the mutant and wildtype led to a significant loss in the CNP-dependent cGMP response compared with that of the empty vector and wildtype, indicating a dominant-negative effect.
In a Dutch mother and her 2 daughters with Miura-type epiphyseal chondrodysplasia (ECDM; 615923), Lauffer et al. (2020) identified heterozygosity for a 6-bp deletion (c.1444_1449delATGCTG, NM_003995.3) in exon 8 of the NPR2 gene, resulting in deletion of 2 highly conserved amino acids (Met482 and Leu483) within the submembrane region. The mutation was identified by direct sequencing of the NPR2 gene. Testing in fibroblasts from the mother and in HEK293 cells transfected with the mutant NPR2 demonstrated that basal and CNP-stimulated cGMP levels were increased compared to controls.
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