Alternative titles; symbols
HGNC Approved Gene Symbol: PAPPA
Cytogenetic location: 9q33.1 Genomic coordinates (GRCh38): 9:116,153,791-116,402,321 (from NCBI)
By PCR using degenerate primers based on purified PAPPA peptide fragments, followed by screening 2 placenta cDNA libraries, Kristensen et al. (1994) cloned a cDNA encoding proPAPPA. The deduced proprotein contains 1,551 amino acids, and cleavage at an N-terminal RxxR motif results in a mature 1,547-amino acid protein. The N-terminal half contains 2 approximately 26-amino acid lin-notch repeats, followed by a putative metalloprotease-like zinc-binding site. The C-terminal half contains 5 approximately 60-amino acid motifs related to the short consensus repeats of complement proteins and selectins, as well as a third lin-notch repeat. PAPPA also has 14 putative N-glycosylation sites, 7 putative O-glycosylation sites, and 82 cysteine residues, all of which are involved in disulfide bonding. Northern blot analysis detected a major transcript of about 12 kb and a minor transcript of about 8.5 kb in placenta. No expression was detected in heart, lung, skeletal muscle, brain, liver, kidney, and pancreas.
Haaning et al. (1996) determined that the full-length preproPAPPA contains 1,627 amino acids. It has a putative 22-amino acid signal peptide, followed by a highly basic arginine-rich propeptide of 58 amino acids. The cDNA contains an extremely high GC content and has an unusually long 5-prime UTR with several upstream short open reading frames. Sequences in the 5-prime UTR are identical to a cAMP-inducible cDNA isolated from a choriocarcinoma cell line and an EST isolated from brain.
In transient transfection experiments in HEK293 cells, Overgaard et al. (2000) expressed and purified recombinant PAPPA and found it was secreted as a homodimer of about 400 kD composed of two 200-kD disulfide-bound subunits.
By 5-prime and 3-prime RACE of a placenta cDNA library, Garcia and Castrillo (2005) cloned a short transcript from the 3-prime end of the PAPPA gene, DIPLA1, and a DIPLA1 antisense transcript, DIPAS (610689). Both transcripts are encoded by a single exon and contain several upstream open reading frames. Northern blot analysis of placenta using a DIPLA1 probe detected transcripts of 1.2, 1.8, and 2.7 kb, and RT-PCR showed DIPLA1 expression only in placenta.
Pregnancy-associated plasma protein A (PAPPA) is a large zinc glycoprotein of placental origin. The amino acid sequence deduced from the cDNA shows conserved motifs resembling the short consensus repeats (SCRs) of complement control proteins. The maternal serum level of PAPPA increases exponentially until term. PAPPA is found in the ovarian follicles, follicular fluid, luteal cells, and fallopian tubes of nonpregnant women and in the seminal vesicles and seminal fluid of males. Because low serum levels of PAPPA have been demonstrated in first-trimester pregnancies associated with chromosomally abnormal fetuses, PAPPA has been suggested as a potential biochemical marker for such pregnancies. Westergaard et al. (1983) found complete absence of PAPPA in both maternal serum and placental tissue from a pregnancy with Cornelia de Lange syndrome (122470).
Oxvig et al. (1993) analyzed tryptic peptides from circulating PAPPA and found sequences that exactly matched 3 predicted tryptic peptides from proMBP (see 605601), suggesting that proMBP is a constituent of circulating PAPPA. Sequence analysis and denaturing gel chromatography of PAPPA/proMBP confirmed the finding. Oxvig et al. (1993) concluded that circulating PAPPA is a disulfide-bridged complex with proMBP in which the subunits of the constituents are present in a 1:1 molar ratio.
Proteolytic cleavage of insulin-like growth factor (IGF)-binding proteins is a powerful means of rapid structure and function modification of these important growth-regulatory proteins. Intact IGFBP4 (146733) is a potent inhibitor of IGF action in vitro, and cleavage of IGFBP4 abolishes its ability to inhibit IGF stimulatory effects in a variety of systems, suggesting that IGFBP4 proteolysis acts as a positive regulator of IGF bioavailability. Lawrence et al. (1999) isolated an IGF-dependent IGFBP4-specific protease from human fibroblast-conditioned media and identified it as PAPPA. IGFBP4 protease/PAPPA is a member of the metzincin family of metalloproteases.
Overgaard et al. (2000) compared the proteolytic activity of recombinant PAPPA and pregnancy serum PAPPA/proMBP complex and observed a greater than 100-fold difference, showing that proMBP functions as a proteinase inhibitor in vivo. Polyclonal antibodies against PAPPA abrogated all detectable IGFBP4 proteolytic activity in pregnancy serum, indicating that PAPPA is the dominant, if not the only, IGFBP4 proteinase present in the circulation. Overgaard et al. (2000) showed that pregnancy serum and plasma contained traces (less than 1%) of uncomplexed PAPPA with a much higher specific activity than the PAPPA/proMBP complex, and suggested that the measurable activity of the PAPPA/proMBP complex probably results from the presence of a minor subpopulation of partly inhibited PAPPA that exists in a 2:1 complex with proMBP. Overgaard et al. (2000) stated that inhibition of PAPPA by proMBP represented a novel inhibitory mechanism with the enzyme irreversibly bound to its inhibitor by disulfide bonds.
Hourvitz et al. (2000) identified the cellular sites of PAPPA gene expression in normal human ovaries by in situ hybridization. PAPPA mRNA was low or undetectable in preantral follicles, small (1 to 2 mm) healthy and atretic antral follicles, larger atretic antral follicles, surface epithelium, tunica albuginea, and connective tissue cells. In contrast, an intense PAPPA hybridization signal was evident in the healthy antral follicles examined from 5 mm to the preovulatory stage. In these follicles, the signal was restricted to the granulosa cells. An intense signal for PAPPA mRNA was also present in healthy corpora lutea, being localized to a subset of large luteal cells. The restricted pattern of PAPPA expression in normal human ovaries suggests that PAPPA may be a functional marker of the dominant follicle and its product, the corpus luteum.
Pregnancy
Smith et al. (2002) performed a prospective, multicenter, noninterventional cohort study of 4,288 women at 8 to 12 weeks' gestation who ultimately had uncomplicated singleton pregnancies and delivered normal, live babies at full term. Using multivariate logistic regression (adjusting for maternal height, race, body mass index, smoking status, and elective delivery), a one log at the base 10 unit increase in first trimester PAPPA multiples of the appropriate gestational median (roughly equivalent to the range from the 1st to the 99th percentile) was associated with an 80% reduction in the risk of a low birth weight baby (adjusted odds ratio 0.2; 95% CI, 0.1-0.6; P = 0.002). In a multivariate proportional hazards model, there was a strongly additive and inverse relationship between levels of PAPPA and free beta-CG, and the likelihood of spontaneous labor on any given day of gestation at full term. Smith et al. (2002) concluded that the risk of delivering a low birth weight baby at full term may be determined by the placental activity of insulin-like growth factors in very early pregnancy.
Smith et al. (2002) studied the risk of adverse perinatal outcome among 8,839 women recruited to a multicenter, prospective cohort study of maternal circulating concentrations of trophoblast-derived proteins at 8 to 14 weeks' gestation. Women with PAPPA in the lowest 5th percentile at 8 to 14 weeks' gestation had an increased risk of intrauterine growth restriction, extremely premature delivery, moderately premature delivery, preeclampsia, and stillbirth. The strengths of the associations were similar when the test was performed before 13 weeks' gestation or between 13 and 14 weeks' gestation.
Using DNA microarrays to examine gene expression patterns in normal human placenta, Sood et al. (2006) found that PAPPA is highly expressed in the villus regions.
Coronary Artery Disease
Bayes-Genis et al. (2001) examined the expression level of PAPPA in 8 culprit unstable coronary plaques and 4 stable plaques from 8 patients who had died suddenly of cardiac causes, and they found that PAPPA was abundantly expressed in plaque cells and extracellular matrix of ruptured and eroded plaques but not in stable plaques. In 56 patients with cardiac disease and 13 nonatherosclerotic controls, Bayes-Genis et al. (2001) measured circulating levels of PAPPA, C-reactive protein (CRP; 123260), IGF1 (147440), the MB isoform of creatine kinase (see 123310), and troponin I (TNNI3; 191044). Circulating PAPPA levels were significantly higher in patients with unstable angina or acute myocardial infarction than in patients with stable angina and controls. PAPPA levels correlated with levels of CRP and free IGF1 but not with the markers of myocardial injury, troponin I and CK-MB. Bayes-Genis et al. (2001) concluded that PAPPA is a candidate marker of unstable angina and myocardial infarction.
In 64 asymptomatic hyperlipidemic men and 25 normolipidemic male controls, Beaudeux et al. (2003) observed no difference in serum PAPPA levels between hyperlipidemic and normolipidemic individuals or between hyperlipidemic individuals with carotid artery stenosis and those without. However, among individuals with atheromatous carotid plaques, those with hyperechoic or isoechoic lesions had significantly higher PAPPA levels than those with hypoechoic lesions and normolipidemic controls. Beaudeux et al. (2003) suggested that elevated serum PAPPA levels may be a marker of the degree of echogenicity of carotid atherosclerotic plaque in asymptomatic patients and of an enhanced local inflammatory state involving remodeling of subendothelial extracellular matrix.
Lund et al. (2003) followed 136 consecutive patients who were hospitalized with acute coronary syndrome and remained troponin-negative for 24 hours. During a 6-month follow-up, an elevated serum PAPPA level was found to be an independent predictor of adverse outcome (revascularization, myocardial infarction, or cardiovascular death), as was admission CRP level. Lund et al. (2003) concluded that circulating PAPPA is a strong independent predictor of ischemic cardiac events and need for revascularization in patients who present with suspected myocardial infarction but remain troponin-negative.
In 322 patients with stable angina, Cosin-Sales et al. (2004) assessed their coronary stenoses as complex or smooth and determined PAPPA, proMBP, and CRP serum levels. Patients with complex coronary stenoses had significantly higher PAPPA/proMBP ratios and PAPPA levels than those without. Multiple regression analysis showed that male gender, age, severe coronary artery disease, and PAPPA/proMBP ratio were independent predictors of the number of angiographically complex stenoses. Cosin-Sales et al. (2004) concluded that in patients with stable angina, PAPPA and PAPPA/proMBP ratio are associated with angiographic plaque complexity.
Using a 3.7-kb partial PAPPA cDNA probe for fluorescence in situ hybridization, Silahtaroglu et al. (1993) assigned the PAPPA gene to chromosome 9q33.1. By interspecific backcross linkage analysis, Pilz et al. (1995) mapped the Pappa gene to mouse chromosome 4.
Bayes-Genis, A., Conover, C. A., Overgaard, M. T., Bailey, K. R., Christiansen, M., Holmes, D. R., Jr., Virmani, R., Oxvig, C., Schwartz, R. S. Pregnancy-associated plasma protein A as a marker of acute coronary syndromes. New Eng. J. Med. 345: 1022-1029, 2001. [PubMed: 11586954] [Full Text: https://doi.org/10.1056/NEJMoa003147]
Beaudeux, J.-L., Burc, L., Imbert-Bismut, F., Giral, P., Bernard, M., Bruckert, E., Chapman, M. J. Serum plasma pregnancy-associated protein A: a potential marker of echogenic carotid atherosclerotic plaques in asymptomatic hyperlipidemic subjects at high cardiovascular risk. Arterioscler. Thromb. Vasc. Biol. 23: e7-e10, 2003. [PubMed: 12524241] [Full Text: https://doi.org/10.1161/01.atv.0000047448.76485.b8]
Cosin-Sales, J., Christiansen, M., Kaminski, P., Oxvig, C., Overgaard, M. T., Cole, D., Holt, D. W., Kaski, J. C. Pregnancy-associated plasma protein A and its endogenous inhibitor, the proform of eosinophil major basic protein (proMBP), are related to complex stenosis morphology in patients with stable angina pectoris. Circulation 109: 1724-1728, 2004. [PubMed: 15023879] [Full Text: https://doi.org/10.1161/01.CIR.0000124716.67921.D2]
Garcia, J., Castrillo, J.-L. Identification of two novel human genes, DIPLA1 and DIPAS, expressed in placenta tissue. Gene 344: 241-250, 2005. [PubMed: 15656990] [Full Text: https://doi.org/10.1016/j.gene.2004.10.004]
Haaning, J., Oxvig, C., Overgaard, M. T., Ebbesen, P., Kristensen, T., Sottrup-Jensen, L. Complete cDNA sequence of preproform of human pregnancy-associated plasma protein-A: evidence for expression in the brain and induction by cAMP. Europ. J. Biochem. 237: 159-163, 1996. [PubMed: 8620868] [Full Text: https://doi.org/10.1111/j.1432-1033.1996.0159n.x]
Hourvitz, A., Widger, A. E., Filho, F. L. T., Chang, R. J., Adashi, E. Y., Erickson, G. F. Pregnancy-associated plasma protein-A gene expression in human ovaries is restricted to healthy follicles and corpora lutea. J. Clin. Endocr. Metab. 85: 4916-4919, 2000. [PubMed: 11134163] [Full Text: https://doi.org/10.1210/jcem.85.12.7169]
Kristensen, T., Oxvig, C., Sand, O., Moller, N. P. H., Sottrup-Jensen, L. Amino acid sequence of human pregnancy-associated plasma protein-A derived from cloned cDNA. Biochemistry 33: 1592-1598, 1994. [PubMed: 7508748] [Full Text: https://doi.org/10.1021/bi00172a040]
Lawrence, J. B., Oxvig, C., Overgaard, M. T., Sottrup-Jensen, L., Gleich, G. J., Hays, L. G., Yates, J. R., III, Conover, C. A. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proc. Nat. Acad. Sci. 96: 3149-3153, 1999. [PubMed: 10077652] [Full Text: https://doi.org/10.1073/pnas.96.6.3149]
Lund, J., Qin, Q.-P., Ilva, T., Pettersson, K., Voipio-Pulkki, L.-M., Porela, P., Pulkki, K. Circulating pregnancy-associated plasma protein A predicts outcome in patients with acute coronary syndrome but no troponin I elevation. Circulation 108: 1924-1926, 2003. [PubMed: 14530192] [Full Text: https://doi.org/10.1161/01.CIR.0000096054.18485.07]
Overgaard, M. T., Haaning, J., Boldt, H. B., Olsen, I. M., Laursen, L. S., Christiansen, M., Gleich, G. J., Sottrup-Jensen, L., Conover, C. A., Oxvig, C. Expression of recombinant human pregnancy-associated plasma protein-A and identification of the proform of eosinophil major basic protein as its physiological inhibitor. J. Biol. Chem. 275: 31128-31133, 2000. [PubMed: 10913121] [Full Text: https://doi.org/10.1074/jbc.M001384200]
Oxvig, C., Sand, O., Kristensen, T., Gleich, G. J., Sottrup-Jensen, L. Circulating human pregnancy-associated plasma protein-A is disulfide-bridged to the proform of eosinophil major basic protein. J. Biol. Chem. 268: 12243-12246, 1993. [PubMed: 7685339]
Pilz, A., Woodward, K., Povey, S., Abbott, C. Comparative mapping of 50 human chromosome 9 loci in the laboratory mouse. Genomics 25: 139-149, 1995. [PubMed: 7774911] [Full Text: https://doi.org/10.1016/0888-7543(95)80119-7]
Silahtaroglu, A. N., Tumer, Z., Kristensen, T., Sottrup-Jensen, L., Tommerup, N. Assignment of the human gene for pregnancy-associated plasma protein A (PAPPA) to 9q33.1 by fluorescence in situ hybridization to mitotic and meiotic chromosomes. Cytogenet. Cell Genet. 62: 214-216, 1993. [PubMed: 7679961] [Full Text: https://doi.org/10.1159/000133479]
Smith, G. C. S., Stenhouse, E. J., Crossley, J. A., Aitken, D. A., Cameron, A. D., Connor, J. M. Early pregnancy levels of pregnancy-associated plasma protein A and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth. J. Clin. Endocr. Metab. 87: 1762-1767, 2002. [PubMed: 11932314] [Full Text: https://doi.org/10.1210/jcem.87.4.8430]
Smith, G. C. S., Stenhouse, E. J., Crossley, J. A., Aitken, D. A., Cameron, A. D., Connor, J. M. Early-pregnancy origins of low birth weight. Nature 417: 916 only, 2002. [PubMed: 12087395] [Full Text: https://doi.org/10.1038/417916a]
Sood, R., Zehnder, J. L., Druzin, M. L., Brown, P. O. Gene expression patterns in human placenta. Proc. Nat. Acad. Sci. 103: 5478-5483, 2006. [PubMed: 16567644] [Full Text: https://doi.org/10.1073/pnas.0508035103]
Westergaard, J. G., Chemnitz, J., Teisner, B., Poulsen, H. K., Ipsen, L., Beck, B., Grudzinskas, J. G. Pregnancy-associated plasma protein A: a possible marker in the classification and prenatal diagnosis of Cornelia de Lange syndrome. Prenatal Diag. 3: 225-232, 1983. [PubMed: 6194522] [Full Text: https://doi.org/10.1002/pd.1970030307]