Alternative titles; symbols
HGNC Approved Gene Symbol: NPPA
Cytogenetic location: 1p36.22 Genomic coordinates (GRCh38): 1:11,845,709-11,847,783 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.22 | Atrial fibrillation, familial, 6 | 612201 | Autosomal dominant | 3 |
| Atrial standstill 2 | 615745 | Autosomal recessive | 3 |
From human as well as rat atrial tissue, peptides of natriuretic-diuretic activity have been identified and implicated in the control of extracellular fluid volume and electrolyte homeostasis. There are multiple forms of these so-called atrial natriuretic polypeptides (ANP), ranging in molecular mass from 3 to 13 kD, and it has been suggested that all may derive from the same precursor. Working from established amino acid sequence of human alpha-ANP, a 28-residue peptide with potent natriuretic action, Oikawa et al. (1984) elucidated the structure of its precursor and the gene encoding it. The cDNA encodes gamma-ANP, a polypeptide of 13 kD, whose C-terminal 28 amino acids are processed as alpha-ANP. From the work of Zivin et al. (1984), atrial natriuretic factor (ANF) appears to be synthesized as a large precursor, atrial pronatriodilatin. The cDNA has an open reading frame potentially encoding a protein of 152 amino acids, of which the first 24 amino acids strongly resemble a signal sequence. This is followed by a sequence with 80% homology to a second vasoactive protein, porcine cardiodilatin. The ANF peptide is contained in the COOH-terminal portion of the protein.
The diagram of silver grains from the in situ hybridization studies of Yang-Feng et al. (1985) suggested localization of ANP in 1p36.2; 1p36.3 carried the next most grains, with 1p36.1 in third place.
Quirion et al. (1986) found high density of ANP binding sites in various regions of the brain and suggested the existence of a family of heart-brain peptides, in analogy to the well-known brain-gut peptides. Furthermore, the wide distribution of ANP binding sites suggested that the role of ANP may not be limited to central regulation of cardiovascular functions.
Johansson et al. (1987) showed that the amyloid that is commonly deposited in the atria in older persons has the immunologic properties of ANP and is presumably derived from that peptide.
Sachse et al. (1988) reported on the construction of synthetic ANF genes for both the human and rat molecules. The synthetic genes were cloned into the beta-galactosidase gene of plasmid pUR289 and used in an expression system to form fusion proteins which were immunoreactive with anti-ANF antiserum.
During heart development, chamber myocardium forms locally from the embryonic myocardium of the tubular heart, and expression of the ANF gene is one of the first hallmarks of chamber formation. Habets et al. (2002) showed that a fragment within the regulatory region of mouse Anf was responsible for the developmental pattern of Anf gene expression, and part of this fragment repressed cardiac troponin I (see TNNI3; 191044) activity specifically in the atrioventricular canal. In vivo inactivation of an Nk2 (see NKX2E; 600584) homeobox factor-binding element (NKE) or a T-box factor (see TBX2; 600747)-binding element (TBE) within the Anf fragment removed troponin repression in the embryonic myocardium of the atrioventricular canal, but did not alter troponin repression in the chamber myocardium. Habets et al. (2002) also found that Tbx2 expression in the developing heart was restricted to areas complementary to Anf expression. Tbx2 and Nkx2e formed a complex on the TBE-NKE site within the Anf promoter fragment and repressed Anf activity.
Atrial Fibrillation 6
In affected members of a 3-generation family with autosomal dominant atrial fibrillation mapping to chromosome 1p36-p35 (ATFB6; 612201), Hodgson-Zingman et al. (2008) identified a 2-bp deletion (108780.0001) in the NPPA gene. The mutation, predicted to generate a fusion protein of the normal mature peptide plus an anomalous 12 residues in the C terminus, segregated with disease and was not found in 560 controls.
In a cohort of 231 patients with atrial fibrillation, Abraham et al. (2010) analyzed the KCNQ1 (607542) and NPPA genes and identified heterozygosity for a missense mutation in NPPA (S64R; 108780.0002) in the proband of a Caucasian kindred segregating early-onset lone AF. The missense mutation segregated with disease in the family and was not found in Caucasian, Han Chinese, Asian, or African American population controls. Abraham et al. (2010) also identified a mutation in the KCNQ1 gene (607542.0041) in another AF family (ATFB3; 607554) in the cohort; functional analysis revealed strikingly similar gain-of-function defects associated with the mutants, with atrial action potential shortening and altered calcium current as a common mechanism.
In a cohort of 160 Chinese patients with lone AF and 844 controls, Ren et al. (2010) analyzed the NPPA SNP rs5063 and found significant association with AF (p = 0.015; p = 0.003 after adjusting for age, gender, hypertension, diabetes, and smoking). The minor 'A' allele of rs5063 was found to confer a risk of lone AF with an odds ratio of 1.63, which increased to 1.89 after adjustment. Analysis of genotyping data under an additive, dominant, or recessive model showed significant association with lone AF for both an additive (p = 0.005) and a dominant (p = 0.007) model. Screening of the NPPA gene by direct sequencing revealed 3 probands with mutations that were not found in 844 controls, including 2 mutations in the 3-prime untranslated region and a missense mutation (I138T); however, all 3 families declined further genetic analysis. Ren et al. (2010) concluded that in addition to being a disease-causing gene, NPPA is a susceptibility gene for lone AF.
Atrial Standstill 2
In affected individuals from 6 families from a small community in northeastern Italy with atrial standstill (ATRST2; 615745) mapping to chromosome 1p36, Disertori et al. (2013) sequenced 4 candidate genes and identified homozygosity for a missense mutation in the NPPA gene (R150Q; 108780.0003) that segregated with disease in each family.
To determine if defects in the ANP system can cause hypertension, John et al. (1995) generated mice with a disruption of the Anp gene. Homozygous mutants had no circulating or atrial Anp, and their blood pressures were elevated when they were fed standard and intermediate salt diets. On standard salt diets, heterozygotes had normal amounts of circulating Anp and normal blood pressures. However, on high salt diets, they were hypertensive. These results demonstrate that genetically reduced production of Anp can lead to salt-sensitive hypertension. The findings encourage the search for human genetic variants that affect the function of the ANP system. Detecting such variants may identify hypertensive patients likely to benefit from reduced salt intake.
In affected members of a 3-generation family of northern European ancestry with atrial fibrillation (612201), Hodgson-Zingman et al. (2008) identified heterozygosity for a 2-bp deletion (456delAA) in exon 3 of the NPAA gene, resulting in a frameshift that abolishes the stop codon and is predicted to generate a fusion protein with 12 additional residues in the C terminus. The mutation was not found in unaffected family members or 560 controls. Radioimmunoassay revealed that the mutant peptide was present in the plasma of heterozygotes in concentrations 5- to 10-fold higher than those of wildtype ANP, and shortened atrial action potentials were observed in an isolated heart model.
In affected members of a Caucasian kindred segregating autosomal dominant early-onset lone atrial fibrillation (ATFB6; 602201), Abraham et al. (2010) identified heterozygosity for a c.190A-C transversion in exon 2 of the NPPA gene, resulting in a ser64-to-arg (S64R) substitution at a conserved residue in the proANP peptide. The missense mutation segregated with disease in the family and was not found in Caucasian, Han Chinese, Asian, or African American population controls. Abraham et al. (2010) noted that ANP levels were not significantly different between family members with AF who were mutations carriers and those who were unaffected and did not carry the mutation. Functional analysis in CHO cells demonstrated that coexpression of mutant NPPA with its ancillary subunit KCNE1 (176261) generated a significantly larger current compared to wildtype, which also activated earlier than wildtype currents. The mutant accelerated both activation and deactivation over all voltages. Pretreatment with anantin, a competitive ANP receptor antagonist, completely eliminated current augmentation and acceleration seen with the mutant, indicating that the effect of the S64R fragment on current is mediated by the endogenous ANP receptor.
In affected individuals with atrial standstill (ATRST2; 615745) and atrial dilation from 6 families within a small community in northeastern Italy, 3 of which were originally reported by Disertori et al. (1983), Disertori et al. (2013) identified homozygosity for a c.449G-A transition in exon 2 of the NPPA gene, resulting in an arg150-to-gln (R150Q) substitution at a highly conserved residue in the preproANP. The mutation segregated with disease in each family and was present in heterozygosity in 16 of 192 healthy controls from the same geographic area; however, it was not found in 200 randomly selected Italian controls.
Abraham, R. L., Yang, T., Blair, M., Roden, D. M., Darbar, D. Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation. J. Molec. Cell. Cardiol. 48: 181-190, 2010. [PubMed: 19646991] [Full Text: https://doi.org/10.1016/j.yjmcc.2009.07.020]
Ackermann, U. Structure and function of atrial natriuretic peptides. Clin. Chem. 32: 241-247, 1986. [PubMed: 2935330]
de Bold, A. J. Atrial natriuretic factor: a hormone produced by the heart. Science 230: 767-770, 1985. [PubMed: 2932797] [Full Text: https://doi.org/10.1126/science.2932797]
Disertori, M., Guarnerio, M., Vergara, G., Del Favero A., Bettini, R., Inama, G., Rubertelli, M., Furlanello, F. Familial endemic persistent atrial standstill in a small mountain community: review of eight cases. Europ. Heart J. 4: 354-361, 1983. [PubMed: 6225642] [Full Text: https://doi.org/10.1093/oxfordjournals.eurheartj.a061473]
Disertori, M., Quintarelli, S., Grasso, M., Pilotto, A., Narula, N., Favalli, V., Canclini, C., Diegoli, M., Mazzola, S., Marini, M., Del Greco, M., Bonmassari, R., Mase, M., Ravelli, F., Specchia, C., Arbustini, E. Autosomal recessive atrial dilated cardiomyopathy with standstill evolution associated with mutation of natriuretic peptide precursor A. Circ. Cardiovasc. Genet. 6: 27-36, 2013. [PubMed: 23275345] [Full Text: https://doi.org/10.1161/CIRCGENETICS.112.963520]
Flynn, T. G., Davies, P. L. The biochemistry and molecular biology of atrial natriuretic factor. Biochem. J. 232: 313-321, 1985. [PubMed: 2936330] [Full Text: https://doi.org/10.1042/bj2320313]
Greenberg, B. D., Bencen, G. H., Seilhamer, J. J., Lewicki, J. A., Fiddes, J. C. Nucleotide sequence of the gene encoding human atrial natriuretic factor precursor. Nature 312: 656-658, 1984. [PubMed: 6095119] [Full Text: https://doi.org/10.1038/312656a0]
Habets, P. E. M. H., Moorman, A. F. M., Clout, D. E. W., van Roon, M. A., Lingbeek, M., van Lohuizen, M., Campione, M., Christoffels, V. M. Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Genes Dev. 16: 1234-1246, 2002. [PubMed: 12023302] [Full Text: https://doi.org/10.1101/gad.222902]
Hodgson-Zingman, D. M., Karst, M. L., Zingman, L. V., Heublein, D. M., Darbar, D., Herron, K. J., Ballew, J. D., de Andrade, M., Burnett, J. C., Jr., Olson, T. M. Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. New Eng. J. Med. 359: 158-165, 2008. [PubMed: 18614783] [Full Text: https://doi.org/10.1056/NEJMoa0706300]
Johansson, B., Wernstedt, C., Westermark, P. Atrial natriuretic peptide deposited as atrial amyloid fibrils. Biochem. Biophys. Res. Commun. 148: 1087-1092, 1987. [PubMed: 2961331] [Full Text: https://doi.org/10.1016/s0006-291x(87)80243-7]
John, S. W. M., Krege, J. H., Oliver, P. M., Hagaman, J. R., Hodgin, J. B., Pang, S. C., Flynn, T. G., Smithies, O. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science 267: 679-681, 1995. Note: Erratum: Science 267: 1753 only, 1995. [PubMed: 7839143] [Full Text: https://doi.org/10.1126/science.7839143]
Kennedy, B. P., Marsden, J. J., Flynn, T. G., de Bold, A. J., Davies, P. L. Isolation and nucleotide sequence of a cloned cardionatrin cDNA. Biochem. Biophys. Res. Commun. 122: 1076-1082, 1984. [PubMed: 6236804] [Full Text: https://doi.org/10.1016/0006-291x(84)91201-4]
Lang, R. E., Tholken, H., Ganten, D., Luft, F. C., Ruskoaho, H., Unger, T. Atrial natriuretic factor--a circulating hormone simulated by volume loading. Nature 314: 264-266, 1985. [PubMed: 3157062] [Full Text: https://doi.org/10.1038/314264a0]
Laragh, J. H. Atrial natriuretic hormone, the renin-aldosterone axis, and blood pressure-electrolyte homeostasis. New Eng. J. Med. 313: 1330-1340, 1985. [PubMed: 2932646] [Full Text: https://doi.org/10.1056/NEJM198511213132106]
Maki, M., Parmentier, M., Inagami, T. Cloning of genomic DNA for human atrial natriuretic factor. Biochem. Biophys. Res. Commun. 125: 797-802, 1984. [PubMed: 6097248] [Full Text: https://doi.org/10.1016/0006-291x(84)90609-0]
Napier, M. A., Vandlen, R. L., Albers-Schonberg, G., Nutt, R. F., Brady, S., Lyle, T., Winquist, R., Faison, E. P., Heinel, L. A., Blaine, E. H. Specific membrane receptors for atrial natriuretic factor in renal and vascular tissues. Proc. Nat. Acad. Sci. 81: 5946-5950, 1984. [PubMed: 6091122] [Full Text: https://doi.org/10.1073/pnas.81.19.5946]
Needleman, P., Greenwald, J. E. Atriopeptin: a cardiac hormone intimately involved in fluid, electrolyte, and blood-pressure homeostasis. New Eng. J. Med. 314: 828-834, 1986. [PubMed: 2936957] [Full Text: https://doi.org/10.1056/NEJM198603273141306]
Nemer, M., Chamberland, M., Sirois, D., Argentin, S., Drouin, J., Dixon, R. A. F., Zivin, R. A., Condra, J. H. Gene structure of human cardiac hormone precursor, pronatriodilatin. Nature 312: 654-656, 1984. [PubMed: 6095118] [Full Text: https://doi.org/10.1038/312654a0]
Oikawa, S., Imai, M., Ueno, A., Tanaka, S., Noguchi, T., Nakazato, H., Kangawa, K., Fukuda, A., Matsuo, H. Cloning and sequence analysis of cDNA encoding a precursor for human atrial natriuretic polypeptide. Nature 309: 724-726, 1984. [PubMed: 6203042] [Full Text: https://doi.org/10.1038/309724a0]
Quirion, R., Dalpe, M., Dam, T.-V. Characterization and distribution of receptors for the atrial natriuretic peptides in mammalian brain. Proc. Nat. Acad. Sci. 83: 174-178, 1986. [PubMed: 3001722] [Full Text: https://doi.org/10.1073/pnas.83.1.174]
Ren, X., Xu, C., Zhan, C., Yang, Y., Shi, L., Wang, F., Wang, C., Xia, Y., Yang, B., Wu, G., Wang, P., Li, X., Wang, D., Xiong, X., Liu, J., Liu, Y., Liu, M., Liu, J., Tu, X., Wang, Q. K. Identification of NPPA variants associated with atrial fibrillation in a Chinese GeneID population. Clin. Chim. Acta 411: 481-485, 2010. [PubMed: 20064500] [Full Text: https://doi.org/10.1016/j.cca.2009.12.019]
Sachse, H., Hagendorff, G., Preuss, K. D., Sharma, H. S., Scheit, K. H. Synthesis, molecular cloning and expression of genes coding for atrial natriuretic factors from rat and human. Nucleosides Nucleotides 7: 61-73, 1988.
Seidman, C. E., Bloch, K. D., Klein, K. A., Smith, J. A., Seidman, J. G. Nucleotide sequences of the human and mouse atrial natriuretic factor genes. Science 226: 1206-1209, 1984. [PubMed: 6542248] [Full Text: https://doi.org/10.1126/science.6542248]
Yamaji, T., Ishibashi, M., Takaku, F. Atrial natriuretic factor in human blood. J. Clin. Invest. 76: 1705-1709, 1985. [PubMed: 2932472] [Full Text: https://doi.org/10.1172/JCI112159]
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]
Zivin, R. A., Condra, J. H., Dixon, R. A. F., Seidah, N. G., Chretien, M., Nemer, M., Chamberland, M., Drouin, J. Molecular cloning and characterization of DNA sequences encoding rat and human atrial natriuretic factors. Proc. Nat. Acad. Sci. 81: 6325-6329, 1984. [PubMed: 6238331] [Full Text: https://doi.org/10.1073/pnas.81.20.6325]