WO2009152601A1 - Utilisation du gène (flrg) en tant que marqueur identification d'une d'anomalie foetale - Google Patents

Utilisation du gène (flrg) en tant que marqueur identification d'une d'anomalie foetale Download PDF

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Publication number
WO2009152601A1
WO2009152601A1 PCT/CA2008/002219 CA2008002219W WO2009152601A1 WO 2009152601 A1 WO2009152601 A1 WO 2009152601A1 CA 2008002219 W CA2008002219 W CA 2008002219W WO 2009152601 A1 WO2009152601 A1 WO 2009152601A1
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flrg
marker
level
fetal
biological sample
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PCT/CA2008/002219
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English (en)
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Pierre Miron
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Prenagen Inc.
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/689—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to pregnancy or the gonads
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/36—Gynecology or obstetrics
    • G01N2800/368—Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour

Definitions

  • the present invention concerns the use of follistatin-related gene (FLRG) marker for evaluating an increased risk of fetal abnormality (e.g. trisomy 21 , trisomy 18 or Turner Syndrome) in a pregnant woman.
  • FLRG follistatin-related gene
  • the invention also relates to a noninvasive method for evaluating the increased risk of a pregnant woman to carry a fetus with an abnormality, by measuring the level of FLRG marker in a biological sample from a pregnant woman..
  • prenatal screening involves testing for diseases or conditions in a fetus or embryo before it is born.
  • the goal of the screening is to detect birth defects such as chromosomal aberrations, structural malformations, genetic syndromes or diseases and other conditions.
  • Common procedures to detect these defects include invasive diagnostic procedures such as amniocentesis and chorionic villus sampling (CVS) and non-invasive procedures, such as isolation of fetal cells or nucleotides in maternal blood, and screening tests such as the identification of fetal ultrasound markers and/or the measurement of biochemical or nucleotide markers in the maternal blood.
  • CVS amniocentesis and chorionic villus sampling
  • non-invasive procedures such as isolation of fetal cells or nucleotides in maternal blood
  • screening tests such as the identification of fetal ultrasound markers and/or the measurement of biochemical or nucleotide markers in the maternal blood.
  • Down syndrome i.e. trisomy 21
  • PAPP-A pregnancy-associated plasma protein-A
  • free ⁇ -hCG free-beta-human chorio-gonadotropin
  • NT fetal nuchal translucency
  • a combination of PAPP-A and free ⁇ -hCG with other biochemical markers has been proposed in the first trimester such as, amongst others, inhibin A, human placental lactogen (HPL) and total hCG.
  • biomarkers are also used routinely for the detection of Down syndrome, such as AFP, hCG, free ⁇ -hCG, estriol and inhibin-A.
  • ADAM12 A soluble form of ADAM12 (ADAM12-S), has also been suggested to contribute to the detection of trisomy 21 at an earlier stage in pregnancy, between the 8 th and 12 th weeks of gestation (Laigaard et al., 2003).
  • ADAM12 a disintegrin and metalloprotease, is an IGFBP-3 and IGFBP-5 protease abundantly secreted by the placenta. Concentration of its soluble form, absent in non-pregnant status, is detected very early in maternal serum. In the case of trisomy 21 , levels of ADAM12-S are significantly reduced in maternal serum, particularly between the 8 th and 11 th weeks.
  • ADAM12-S was unlikely to be of much additional value when screening for trisomy 21 in the period between the 11 th and 13 th weeks of gestation, or before the 10 th week of gestation (Spencer, Cowans and Stomatopoulou, 2008; Spencer et al., 2008).
  • An object of the present invention is to fulfil the above-mentioned needs. More specifically, the object is achieved by the use of FLRG as a marker for evaluating an increased risk of fetal abnormality in a biological sample from a pregnant woman.
  • the present invention also provides a method for evaluating an increased risk of fetal abnormality in a pregnant woman, said method comprising: a) comparing a FLRG marker level in a biological sample from a pregnant woman to a reference FLRG marker level obtained from a woman carrying a normal fetus; and b) determining if the level of FLRG marker in said biological sample is different from the level of the reference FLRG marker;
  • determination of a difference is indicative of an increased risk of fetal abnormality in said pregnant woman.
  • the present invention further provides a kit for evaluating an increased risk of fetal abnormality in a pregnant woman, said kit comprising: a) a reference FLRG sample; b) a detecting agent for determining FLRG marker level in a sample to be tested; and c) reagent to determine the FLRG marker level in a biological sample to be tested.
  • Figure 1 illustrates Western blots of FLRG antibodies on human, murine or rat sera, with or without addition of human recombinant FLRG.
  • FLRG follistatin-related gene
  • pregnant woman it is meant the individual carrying one or more offspring, known as a fetus or embryo, inside its uterus. It is known that in humans, childbirth usually occurs about 38 weeks from fertilization; thus, pregnancy lasts about nine months.
  • the expression "gestational age” means the gestational time elapsed from the conception plus about fourteen (14) days. The “gestational age” can be calculated in term of days, weeks, months or trimester. Human pregnancy is somewhat arbitrarily divided into three trimester gestational periods, as a means to simplify reference to the different stages of prenatal development.
  • the first trimester gestational period which extends from the conception to about 13 weeks and 6 days of gestation, carries the highest risk of miscarriage (natural death of embryo or fetus).
  • miscarriage naturally death of embryo or fetus.
  • the second trimester gestational period which extends from about week 14 to about week 24 of gestation, the development of the fetus can be more easily monitored and diagnosed.
  • the beginning of the third and last trimester gestational period often approximates the point of viability, or the ability of the fetus to survive, with or without medical help, outside of the uterus.
  • the prenatal screening of fetal abnormality may be advantageously performed anytime before 24 weeks of pregnancy, preferably between gestational week 11 to 14.
  • fetal stage of prenatal development starts when the major structures have formed and lasts until birth.
  • normal fetus it is meant a fetus that is not known to be affected by or is not expected to develop the fetal abnormality for which the pregnant woman is screened for.
  • FLRG marker refers to a FLRG polypeptide or protein or to a nucleotide sequence encoding a follistatin-related gene (FLRG) in the form of DNA or RNA.
  • the expression “reference marker” or “reference level” refers to a marker or marker level present in a pregnant woman carrying a normal fetus.
  • the “reference marker” level or “reference level” may be determined at the same gestational age as the marker level used to evaluating an increased risk of fetus abnormality.
  • the expression "increased risk” when used in conjunction with "fetus abnormality” means to denote the probability that a fetal abnormality is present in the fetus and/or that the fetus will develop a fetal abnormality.
  • fetal abnormality refers to any disease or disorder which affects the fetus.
  • a “fetal abnormality” may be trisomy 21 , trisomy 18, trisomy 13, open spina bifida, neural tube defects, ventral wall defects, Edwards Syndrome, Patau Syndrome, Turner Syndrome, Monosomy X, triploidies, monoploidies and Klinefelter Syndrome.
  • biological sample refers to, for instance, blood, serum, plasma or placenta from the pregnant woman.
  • samples used for the purposes of the present invention can also come from urine, pleural fluid, saliva, tissues and follicular fluid of the pregnant subject.
  • the procedures used to collect such samples are known to a person skilled in the art and may include, for instance, intravenous methods, procedures using a syringe or biopsy.
  • the expressions "difference in marker levels” or “different from the level” mean that the level of FLRG marker measured in a biological sample is either lower or higher (depending of the evaluated fetus abnormality) than the level of FLRG marker measured in the control or reference sample. The larger is the difference between the levels of FLRG marker, higher may be the risk of fetal abnormality.
  • FLRG as a marker and method of use
  • FLRG Follistatin-related gene
  • a related object of the invention there is provided a method for evaluating an increased risk of fetal abnormality in a pregnant woman.
  • the method comprises the following steps:
  • the comparison between FLRG markers levels is indicative of the pregnant woman's risk of carrying a fetus with a fetal abnormality.
  • the levels of FLRG markers are substantially identical, the woman's risk of carrying a fetus with a fetal abnormality may be low. However, larger the difference in the levels of the FLRG marker is, higher may be the risk of fetal abnormality in the pregnant woman.
  • the measurement of FLRG marker level may be performed by detecting and quantifying the FLRG protein/poly peptide itself and/or the polynucleotide encoding the same within a biological sample.
  • the detection of FLRG may involves a detecting agent, which may be, for instance, a specific antibody such as a purified monoclonal or polyclonal antibody raised against FLRG protein or a polypeptide thereof.
  • the determination of FLRG marker level is achieved by contacting a FLRG specific antibody with the biological sample under suitable conditions to obtain a FLRG- antibody complex.
  • the expression "FLRG-specific antibody” refers to antibodies that bind to one or more epitopes of FLRG protein, but which do not substantially recognize and bind other molecules in a sample containing a mixed population of antigenic molecules.
  • FLRG is quantified in accordance with biochemical assays known by the skilled person in the art of biochemistry and/or analytical chemistry.
  • FLRG marker level may be quantified by immunoassays such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), magnetic immunoassay (MIA) or immunoblot (Western blot).
  • the detecting agent may be labeled for instance with an epitope, such as FLAG, HA-tag, a biotin, a flurophore, a radio-isotope, a dye, or by any other suitable molecule.
  • the amount or concentration of FLRG marker may be estimated by using an appropriate reader.
  • the FLRG protein may be quantified by image analysis or radioacivity count. It is to be understood that any other process known to one skilled in the art for detecting and quantifying the level of FLRG within a biological sample is within the scope of the present invention.
  • a FLRG nucleotide sequence is advantageously sought, such may be achieved, for instance, by a genetic detection means, such as a nucleic acid hybridization process (e.g. Southern blots and Northern blots) or a nucleic acid amplifying process (e.g. polymerase chain reaction (PCR)) so as to detect and quantify specific regions of a RNA or DNA strand of the FLRG marker nucleotide sequence.
  • PCR polymerase chain reaction
  • the detection and quantification of FLRG marker nucleic acid may be achieved by contacting at least one specific DNA or RNA probe or primer with a biological sample under suitable conditions to obtain a specific nucleic acid complex such as DNA-DNA, RNA-DNA or a RNA-RNA.
  • specific nucleic acid complex refers to a probe or a primer that hybridizes specifically to a complementary nucleic acid sequence, but which does not substantially hybridize to other nucleic acid sequence in the same nucleic acid or in other nucleic acids present in the biological sample containing a mixed population of nucleic acids.
  • the expression "under suitable conditions" when referring to a FLRG marker sequence-primer or probe complex means that the contact between the probe or primer and the FLRG nucleic acid in the biological sample is carried out at a temperature and for a period of time in an appropriate reaction mix to allow an effective and specific hybridization between the probe or primer with the FLRG nucleic acid.
  • the number of amplification cycles should be sufficient to obtain a detectable or quantifiable amount of FLRG amplified nucleic acid fragment.
  • the PCR can be a quantitative reverse transcriptase PCR (RT- PCR).
  • primers can be selected from the FLRG cDNA (GenBank accession number U76702).
  • the forward primer may be 5'- TGTGCCTCCGGCAACATTGAC-3'
  • the reverse primer may be 5'- TAGGTGACGTTGTTGTTGCC-3' (Hua-Qin Wang et al. 2003).
  • the quantification of the FLRG marker nucleic acid may be performed, for example but not limited to, by the TaqManTM technology. It is to be understood that any other method or process known to one skilled in the art for detecting and quantifying the level of a nucleic acid within a biological sample is within the scope of the present invention.
  • marker levels can be normalized with respect to gestational age i.e. be converted to gestational age independent values.
  • the normalized value is obtained, for instance, by dividing the marker concentration measured for instance in maternal serum or plasma with the median of the reference value at the same gestational age at which the maternal sample was obtained.
  • the normalized value is called multiple of median (MoM) and may be calculated for use in risk assessment in various conditions, diseases and disorders. MoM is actually a measure indicative of how far an individual test result deviates from the normal population's median (Morin J. F, et al. 2003).
  • the method for evaluating an increased risk of fetal abnormality in a pregnant woman includes measuring the FLRG marker level in said women and comparing the measured FLRG marker levels to a reference level of the same marker in a pregnant woman carrying a normal fetus, after adjustment for confounding variables, such as gestational age, maternal age, weight and smoking status.
  • This comparison may be accomplished using multivariate discriminant analysis technique known to one skilled in the art.
  • Discriminant analysis is a generally known approach to multivariate analysis involving the separation of a population into two or more groups on the basis of probability.
  • the multiple of the median (MoM) approach is advantageously used to determine a fetal abnormality risk.
  • the women carrying trisomy 21 fetuses' data would indicate that the median level of FLRG marker for trisomy 21 is 2.29 times greater in women carrying trisomy 21 fetuses than in women carrying normal fetuses.
  • the level of FLRG marker in the patient's sample is greater than FLRG marker's median in the normal population such as, for example 2.00 multiples of the median greater than the level of FLRG marker level in the controls, one would conclude of an increased risk that fetus has trisomy 21.
  • a patient specific risk assessment could be established in accordance with the methods used to screen for a fetal abnormality including: percentiles; mean plus or minus standard deviation(s); MoM value; or other methods known to those who are skilled in the art.
  • a tested FLRG marker level that is higher or lower than the reference FLRG marker level is indicative of an increased risk of fetal abnormality.
  • the marker levels may advantageously compared at the same gestational and maternal ages.
  • the present invention advantageously provides the prediction and evaluation in the first and/or second trimesters of the risk of fetal abnormality. Particularly, such an evaluation of the risk of fetal abnormality may be given, for instance, from the analysis of the FLRG marker level from a biological sample obtained during a period from the time of conception up to 11 weeks of gestation, or from 11 weeks up to 14 weeks of gestation, or from 14 weeks up to 24 weeks of gestation.
  • the FLRG level in combination with other markers which are currently used for the screening of fetal abnormality.
  • the other marker level is detected and quantified from a pregnant woman and is compared to the level of a corresponding marker level (i.e. reference level) obtained from women carrying normal fetuses. If it is determined that the level of the marker is different from the level of the corresponding reference marker, then this difference is indicative of an increased risk of fetal abnormality in said pregnant woman.
  • the pairing of FLRG marker level with at least one such other marker level provides the advantages of decreasing the false positive screening rate and improving the detection rate of fetal abnormalities.
  • Such additional markers include, for instance but not limited to, alpha feto-protein (AFP), unconjugated oestrol (uE3), human chorionic gonadotrophin (hCG), free alpha sub-unit of hCG (free ⁇ -hCG), free beta sub-unit of hCG (free ⁇ -hCG), beta-core hCG, hyperglycosylated hCG (ITG), placental growth hormonre (PGH), inhibin, preferably dimeric inhibin-A (inhibin A), pregnancy-associated plasma protein A (PAPP-A), complexes of PAPP-A with proMBP (proform of major basic protein), endoglin, ProMBP, disintegrin and metalloprotease 12 (ADAM12), fetal DNA, fetal or placental RNA, ultrasound markers, nuchal translucency, femur length, absence of fetal nasal bone, hyperechogenic bowel, echogenic foci in the heart, choroids plexus cysts, hydrone
  • kits for performing the above-described methods.
  • Such kits typically comprise two or more components necessary for performing such methods.
  • Components may be polynucleotides or polypeptides, reagents, containers and/or equipment.
  • a detecting agent such as a monoclonal antibody or fragment thereof that specifically binds to a FLRG marker protein.
  • Such antibodies or fragments may be provided attached to a support material such as for instance a 96-well plate.
  • One or more additional containers may enclose elements, such as reagents or buffers, to be used in the assay.
  • Such kits may also, or alternatively, contain a detection reagent as described above that contains a reporter group suitable for direct or indirect detection of antibody binding.
  • kits may be designed to detect the level of mRNA or cDNA encoding FLRG marker protein in a biological sample.
  • kits generally comprise at least one oligonucleotide probe or primer, as described above, that hybridizes to a polynucleotide encoding FLRG marker protein.
  • Such an oligonucleotide may be used, for example, within a PCR or hybridization assay. Additional components that may be present within such kits include a second oligonucleotide and/or a reagent or container to facilitate the detection or quantification of a polynucleotide encoding FLRG marker protein.
  • FLRG is an important marker of the increased risk of fetal abnormality.
  • the FLRG marker of the present invention further derives its usefulness as an effective marker for the risk assessment of fetal abnormalities, such as but not limited to, trisomy 21 (Down syndrome), trisomy 18 and Turner syndrome.
  • Example 1 Development of an ELISA test for the measurement of FLRG serum levels in normal or pregnant human patients
  • ELISA enzyme-linked immunosorbent assay
  • rhFLRG recombinant human FLRG
  • the membranes were incubated either with the mouse antibody raised against the human FLRG (MAB1288; R&DTM) diluted at 2 ⁇ g/ml in 5% skimmed milk ( Figure 1 , panel A) or with the goat polyclonal antibodies raised against the human FLRG (BAF1288; R&DTM) at 0.2 ⁇ g/ml diluted in 5% skimmed milk in PBS ( Figure 1 , panel B). Following incubation with the appropriate primary antibody, membranes were washed and incubated with peroxidase-conjugated donkey anti-mouse antibody (#715-036-150,
  • one higher molecular weight band (>170 kDa) could be detected in all serum samples without added recombinant FLRG.
  • a lower doublet ( ⁇ 50 kDa) could be detected in mouse serum.
  • These bands could correspond to the intact immunoglobulin protein and/or chains. This is most likely due to the expected recognition by secondary antibodies used.
  • serum FLRG could not be detected by any of the antibodies.
  • the amount of serum FLRG expected in the serum is rather low (pg) and thus probably not detectable.
  • Microplate was coated overnight at 4 0 C with 100 ⁇ l/well of rat Mab raised against the mouse FLRG (MAB1255; R&DTM) at a concentration of 4 ⁇ g/ml in PBS. Microplate was then washed 3 times in PBS.
  • microplate was incubated with recombinant hFLRG (1288-F3/CF; R&D) diluted in BSA 1% or in human serum for 2 hours at 37 0 C.
  • Microplate was washed and incubated with the biotinylated goat polyclonal antibodies raised against the human FLRG (BAF1288; R&DTM) diluted in BSA 1%, for 1 hour at 37 0 C.
  • microplate was incubated with conjugated streptavidin HRP or Alkaline Phosphatase, (RocklandTM) or alkaline phosphatase anti- goat antibodies (#705-056-147, Jackson ImmunoResearch LaboratoriesTM, Inc.), for 1 hour at 37 °C.
  • the inventor has determined the optimal concentration for each of the reagents used in the ELISA procedure as the maximal amount needed to reach a maximal level of sensitivity.
  • MAB1288 the maximal detection level reached was 3 ng/ml, which is higher than the normal expected level of serum FLRG ( ⁇ 1 ng/ml).
  • the inventor has used MAB1255 instead.
  • MAB1255 is a rat monoclonal antibody that was raised against mouse FLRG, but cross-reacts with the human FLRG. A concentration of 4 ⁇ g/ml was found to be optimal.
  • alkaline phosphatase and horseradish peroxidase conjugated streptavidin gave the same level of sensitivity; however, peroxidase is more likely to give false positive results with serum samples than alkaline phosphatase.
  • Plasma samples obtained from normal and pathological pregnant women, were centrifuged within 30 minutes to obtain the serum and the plasma. Serum and plasma samples were frozen-stored at -72°C immediately after being obtained and until used. Two samples from each of pregnant woman were analyzed: a first tube (plasma) and a second tube (serum).
  • Microplate (CorningTM 9018) is coated overnight at 4 0 C with 100 ⁇ l/well of rat Mab raised against the mouse FLRG (MAB1255; R&DTM) at a concentration of 4 ⁇ g/ml in PBS. Microplate is then washed 3 times in PBS.
  • microplate is incubated with 100 ⁇ l/well of serial dilutions of recombinant hFLRG (1288-F3/CF; R&DTM) diluted either in BSA 1% or in human serum (# 009-000-121 , Jackson ImmunoResearch
  • Samples (100 ⁇ l well) are plated in duplicate at the following dilutions: undiluted, or diluted 1 :2, 1 :4 or 1 :8 in BSA 1%
  • Microplate is washed 3 times in PBS-TweenTM 20 0.05%, once in PBS and then incubated with 100 ⁇ l/well of biotinylated goat polyclonal antibodies raised against the human FLRG (BAF1288; R&DTM) at 0.4 ⁇ g/ml in BSA 1 %, for 1 hour at 37 0 C.
  • microplate is incubated with 100 ⁇ l/well of alkaline phosphatase-conjugated streptavidin (RocklandTM) diluted 1/6000 in BSA 1%, for 1 hour at 37 0 C. 6.
  • substrate pNPP; SigmaTM, 100 ⁇ l/well
  • pNPP pNPP
  • Optical density (O. D.) is read at 405 nm.
  • Plasma samples most often contained a higher concentration of FLRG than serum samples.
  • Plasma FLRG levels were determined at different times in normal pregnancies, between 31 to 262 days of gestation (i.e. 4 to 37 weeks) and between 81 and 101 days of gestation in pathological pregnancies (i.e. between 11-15 weeks; first and second trimesters).
  • FLRG levels measured in maternal plasma ranged from 0,08 to 9,85 ng/ml.
  • FLRG may serve as a maternal risk marker for fetal disease and may therefore be used as a marker of fetal abnormalities.
  • Table 1 Calculated concentration from standard curve in BSA 1 % or human serum (HS) for diluted samples.
  • low means lower than a concentration of 0.5 ng/ml.
  • Table 2 Calculated concentration from standard curves in BSA 1 % for diluted samples and from standard curve in human serum for undiluted samples.
  • low means lower than a concentration of 0.5 ng/ml.
  • Table 3 Calculated concentration from ELISA of FLRG from patients carrying fetus with diagnosed trisomy 18 (T18), trisomy 21 (T21) or Turner syndrome (XO) compared with the calculated concentration of FLRG from normal pregnant women for the control group trisomy 18 (CT18), trisomy 21 (CT21) and Turner syndrome (CXO).
  • the level of ADAM12-S in maternal serum is an early first-trimester marker of fetal trisomy 18. Prenat Diagn, 25, 45-6.
  • PRYOR-KOISHI K., et al., (2007) Overproduction of the follistatin-related gene protein in the placental and maternal serum of women with pre-eclampsia.

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Abstract

L'invention présente concerne le marqueur du gène associé à la follistatine (FLRG) permettant d'évaluer chez une femme enceinte un risque accru d'anomalie foetale (par exemple la trisomie 21, la trisomie 18 ou le syndrome de Turner). L'invention concerne également une méthode non invasive d'évaluation du risque accru couru par femme enceinte de porter un foetus présentant une anomalie, consistant à mesurer le niveau du marqueur FLRG dans un échantillon biologique en provenant.
PCT/CA2008/002219 2008-06-16 2008-12-17 Utilisation du gène (flrg) en tant que marqueur identification d'une d'anomalie foetale WO2009152601A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN103760340A (zh) * 2014-01-28 2014-04-30 成都创宜生物科技有限公司 以flrg作为标志物制备检测工具的应用及检测工具
US10444247B2 (en) 2014-09-17 2019-10-15 Wallac Oy Method for determining the risk of preterm birth

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Title
CIARMELA ET AL.: "Human placenta and fetal membranes express follistatin-related gene mRNA and protein", JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION, vol. 26, no. 7, July 2003 (2003-07-01), pages 641 - 645 *
CUCKLE ET AL.: "Maternal serum activin A and follistatin levels in pregnancies with Down syndrome", PRENATAL DIAGNOSIS, vol. 19, no. 6, 1999, pages 513 - 516 *
SCHNEYER ET AL.: "Follistatin-related protein (FSRP): a new member of the follistatin gene family", MOLECULAR AND CELLULAR ENDOCRINOLOGY, vol. 180, no. 1-2, July 2001 (2001-07-01), pages 33 - 38 *
SIDIS ET AL.: "Follistatin-related protein and follistatin differentially neutralize endogenous vs. exogenous activin", ENDOCRINOLOGY, vol. 143, no. 5, 2002, pages 1613 - 1624 *
WALLACE ET AL.: "Amniotic fluid levels of dimeric inhibins, pro-aC inhibin, activin A and follistatin in Down's syndrome", CLINICAL ENDOCRINOLOGY, vol. 50, no. 5, 1999, pages 669 - 673 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103760340A (zh) * 2014-01-28 2014-04-30 成都创宜生物科技有限公司 以flrg作为标志物制备检测工具的应用及检测工具
CN103760340B (zh) * 2014-01-28 2016-11-23 成都创宜生物科技有限公司 以flrg作为标志物制备检测工具的应用及检测工具
US10444247B2 (en) 2014-09-17 2019-10-15 Wallac Oy Method for determining the risk of preterm birth
US11255861B2 (en) 2014-09-17 2022-02-22 Wallac Oy Method for determining the risk of preterm birth

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