The proform of eosinophil major basic protein: a new maternal serum marker for Down syndrome

Christiansen, Michael; Oxvig, Claus; Wagner, Jill M.; Qin, Qiuping; Nguyen, Tam T. T. N.; Overgaard, Michael Toft; Larsen, Severin Olesen; Sottrup‐Jensen, Lars; Gleich, Gerald J.; Nørgaard‐Pedersen, Bent

doi:10.1002/(sici)1097-0223(199910)19:10<905::aid-pd658>3.0.co;2-q

Cited by 32 publications

(16 citation statements)

References 42 publications

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“…The inhibin A concentration in maternal serum is reduced in week 7-8 and increased in week 9-11 in DS pregnancies compared with normal pregnancies. This finding is comparable to the findings for SP1 (25,26), proMBP (27), hCG (28) and PAPP-A (29), but for these markers, the transitions between reduced and elevated/normal in DS pregnancies occur in week 10-12, 10-12, 7-8 and 14-15, respectively. The transition has not been explained, but it seems to be a general mechanism.…”

Section: Discussionsupporting

confidence: 87%

Inhibin A is a maternal serum marker for Down's syndrome early in the first trimester

Christiansen

Nørgaard‐Pedersen

2005

Clinical Genetics

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Inhibin A is a maternal serum marker for fetal Down's syndrome (DS) in the second trimester. We examined whether inhibin A could be used early in the first trimester. Maternal serum concentrations of inhibin A were determined in 81 controls and 27 cases of fetal trisomy 21 in gestational week 5-11. The log MoM (Multiple of the Median of normal pregnancies) inhibin A concentration in DS pregnancies increased with gestational age (p = 0.001) from a mean log MoM (standard deviation) of -0.1754 (0.3712) (n = 11) in week 7-8 to a mean log MoM (standard deviation) of 0.1842 (0.2145) (n = 12) in week 9-11. This corresponded to an increase in inhibin median MoM from 0.67 to 1.53. When inhibin A was used together with pregnancy-associated plasma protein-A, free beta-human chorionic gonadotrophin and nuchal translucency as DS markers, the estimated detection rates were 81.4 and 82.6% in weeks 7-8 and 9-11, respectively, for false-positive rates of 0.9 and 1.0%. The performance of the latter combination early in the first trimester is nearly as good as that of integrated first- and second-trimester screening, with the further advantage that the risk can be reported to the pregnant woman in first trimester.

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Section: Discussionsupporting

confidence: 87%

Inhibin A is a maternal serum marker for Down's syndrome early in the first trimester

Christiansen

Nørgaard‐Pedersen

2005

Clinical Genetics

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“…18 The proform of eosinophil major basic protein has been identified as a maternal serum marker for Down syndrome. 19 consists of seven exons, of which exons 1 to 4 can be alternatively transcribed. 27 Deletion of exons 5 and 6 from the mouse Rcan1 gene leads to deficiency of the Rcan1 protein.…”

Section: Mice Bone Marrow Cells From Rcan1mentioning

confidence: 99%

Regulator of Calcineurin 1 (Rcan1) Is Required for the Development of Pulmonary Eosinophilia in Allergic Inflammation in Mice

Yang

MacNeil

Junkins

et al. 2011

The American Journal of Pathology

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The presence of eosinophils in the lung is often regarded as a defining feature of asthma. On allergen stimulation, numbers of eosinophils and their progenitors are increased in both the bone marrow and lungs. Eosinophil progenitors provide an ongoing supply of mature eosinophils. Here, we report that deficiency in the regulator of calcineurin 1 gene (Rcan1) leads to a near-complete absence of eosinophilia in ovalbumin-induced allergic asthma in mice. In the absence of Rcan1, bone marrow cells produce significantly fewer eosinophils in vivo and in vitro on interleukin-5 stimulation. Importantly, eosinophil progenitor populations are significantly reduced in both naïve and ovalbumin-challenged Rcan1 mice. Bone marrow cells from Rcan1؊/؊ mice are capable of developing into fully mature eosinophils, suggesting that Rcan1 is required for eosinophil progenitor production but may not be necessary for eosinophil maturation. Thus, Rcan1 represents a novel contributor in the development of eosinophilia in allergic asthma through regulation of eosinophil progenitor production.

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“…For immunovisualization, blots were blocked with 2 % Tween 20 and equilibrated in 50 mM Tris\HCl\500 mM NaCl\0.1 % Tween 20, pH 9.0 (Tris\saline\Tween, TST). Monoclonal antibody [27] (mAb 234-2, for detection of unreduced PAPP-A) or polyclonal antibodies [28] (for detection of reduced or unreduced PAPP-A) were used. The antibodies were diluted in TST containing 0.5 % fetal bovine serum, and blots were incubated for 1 h at 37 mC.…”

Section: Miscellaneous Proceduresmentioning

confidence: 99%

“…The levels of recombinant PAPP-A in the supernatants were measured by a standard sandwich ELISA as described previously [13]. For sequence analysis of PAPP-A fragments generated by autocleavage, antigen was affinity-purified on anti-PAPP-A\proMPB [28] immobilized on CNBr-activated Sepharose (Pharmacia) according to the manufacturer's protocol. Bound protein was eluted with 200 mM glycine, pH 2.2, separated on 10-20 % reducing SDS\PAGE, blotted on to a PVDF membrane and stained with Coomassie Brilliant Blue.…”

Section: Miscellaneous Proceduresmentioning

confidence: 99%

Mutational analysis of the proteolytic domain of pregnancy-associated plasma protein-A (PAPP-A): classification as a metzincin

Boldt

Overgaard

Laursen

et al. 2001

Biochemical Journal

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119

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The bioavailability of insulin-like growth factor (IGF)-I and -II is controlled by six IGF-binding proteins (IGFBPs 1–6). Bound IGF is not active, but proteolytic cleavage of the binding protein causes release of IGF. Pregnancy-associated plasma protein-A (PAPP-A) has recently been found to cleave IGFBP-4 in an IGF-dependent manner. To experimentally support the hypothesis that PAPP-A belongs to the metzincin superfamily of metalloproteinases, all containing the elongated zinc-binding motif HEXXHXXGXXH (His-482–His-492 in PAPP-A), we expressed mutants of PAPP-A in mammalian cells. Substitution of Glu-483 with Ala causes a complete loss of activity, defining this motif as part of the active site of PAPP-A. Interestingly, a mutant with Glu-483 replaced by Gln shows residual activity. Known metzincin structures contain a so-called Met-turn, whose strictly conserved Met residue is thought to interact directly with residues of the active site. By further mutagenesis we provide experimental evidence that Met-556 of PAPP-A, 63 residues from the zinc-binding motif, is located in a Met-turn of PAPP-A. Our hypothesis is also supported by secondary-structure prediction, and the ability of a 55-residue deletion mutant (d[S498-Y552]) to express and retain antigenecity. However, because PAPP-A differs in the features defining the individual established metzincin families, we suggest that PAPP-A belongs to a separate family. We also found that PAPP-A can undergo autocleavage, and that autocleaved PAPP-A is inactive. A lack of unifying elements in the sequences around the found cleavage sites of PAPP-A and a variant suggests steric regulation of substrate specificity.

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The proform of eosinophil major basic protein: a new maternal serum marker for Down syndrome

Cited by 32 publications

References 42 publications

Inhibin A is a maternal serum marker for Down's syndrome early in the first trimester

Inhibin A is a maternal serum marker for Down's syndrome early in the first trimester

Regulator of Calcineurin 1 (Rcan1) Is Required for the Development of Pulmonary Eosinophilia in Allergic Inflammation in Mice

Mutational analysis of the proteolytic domain of pregnancy-associated plasma protein-A (PAPP-A): classification as a metzincin

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