Dataset Information

Analysis of genes coding for CD46, CD55, and C4b-binding protein in patients with idiopathic, recurrent, spontaneous pregnancy loss.

ABSTRACT: Since a tightly regulated complement system is needed for a successful pregnancy, we hypothesized that alterations in complement inhibitors may be associated with idiopathic, recurrent miscarriage. We sequenced all exons coding for three complement inhibitors: C4b-binding protein (C4BP), CD46, and CD55 in 384 childless women with at least two miscarriages that could not be explained by known risk factors. Several alterations were found in C4BPA, of which the R120H, I126T, and the G423T mutations affected the expression level and/or the ability of recombinant C4BP to serve as cofactor for factor I. The only variant in C4BPB was located in the C-terminal part, and did not impair the polymerization of the molecule. Our results identify for the first time alterations in C4BP in women experiencing recurrent miscarriages. We also found four CD46 alterations in individual patients that were not found in healthy controls. One of the rare variants, P324L, showed decreased expression, whereas N213I resulted in deficient protein processing as well as an impaired cofactor activity in the degradation of both C4b and C3b. The identified alterations may result in in vivo consequences and contribute to the disorder but the degree of association must be evaluated in larger cohorts.

SUBMITTER: Mohlin FC

PROVIDER: S-EPMC3760018 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Analysis of genes coding for CD46, CD55, and C4b-binding protein in patients with idiopathic, recurrent, spontaneous pregnancy loss.

Mohlin Frida C FC Mercier Eric E Fremeaux-Bacchi Veronique V Liszewski M Kathryn MK Atkinson John P JP Gris Jean-Christophe JC Blom Anna M AM

European journal of immunology 20130423 6

Since a tightly regulated complement system is needed for a successful pregnancy, we hypothesized that alterations in complement inhibitors may be associated with idiopathic, recurrent miscarriage. We sequenced all exons coding for three complement inhibitors: C4b-binding protein (C4BP), CD46, and CD55 in 384 childless women with at least two miscarriages that could not be explained by known risk factors. Several alterations were found in C4BPA, of which the R120H, I126T, and the G423T mutations ...[more]

PMID: 23508668

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Project description:Miscarriage is the most common complication of pregnancy. Approximately 1% of couples trying to conceive will experience recurrent miscarriages, defined as three or more consecutive pregnancy losses and many of these cases remain idiopathic. Complement is implicated both in the physiology and pathology of pregnancy. Therefore, we hypothesized that alterations in the C3 gene could potentially predispose to this disorder. We performed full Sanger sequencing of all exons of C3, in 192 childless women, with at least two miscarriages and without any known risk factors. All exons carrying non-synonymous alterations found in the patients were then sequenced in a control group of 192 women. None of the identified alterations were significantly associated with the disorder. Thirteen identified non-synonymous alterations (R102G, K155Q, L302P, P314L, Y325H, V326A, S327P, V330I, K633R, R735W, R1591G, G1606D, and S1619R) were expressed recombinantly, upon which C3 expression and secretion were determined. The L302P and S327P were not secreted from the cells, likely due to misfolding and intracellular degradation. Y325H, V326A, V3301I, R1591G, and G1606D yielded approximately half C3 concentration in the cell media compared with wild type (WT). We analyzed the hemolytic activity of the secreted C3 variants by reconstituting C3-depleted serum. In this assay, R1591G had impaired hemolytic activity while majority of remaining mutants instead had increased activity. R1591G also yielded more factor B activation in solution compared with WT. R1591G and G1606D showed impaired degradation by factor I, irrespectively if factor H, CD46, or C4b-binding protein were used as cofactors. These two C3 mutants showed impaired binding of the cofactors and/or factor I. Taken together, several alterations in C3 were identified and some of these affected the secretion and/or the function of the protein, which might contribute to the disorder but the degree of association must be evaluated in larger cohorts.

Project description:ObjectiveMicroRNAs (miRNAs) regulate gene expression during the peri-implantation period. The purpose of this study was to investigate whether genetic polymorphisms in the four miRNAs associated with fetal or placental development play roles in the development of idiopathic recurrent pregnancy loss (RPL) in Korean females.Study designA case-control study involving 225 controls and 387 women with at least two consecutively recurrent pregnancy losses between 1999 and 2012 was performed. The genotypes of the four miRNA polymorphisms, including miR-27a rs895819, miR-423 rs6505162, miR-449b rs10061133, and miR-605 rs2043556, were analyzed by the polymerase chain reaction-restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals were estimated using multivariate analyses after maternal age adjustments. The relationships between each of the four microRNA genotypes and each of the six clinical parameters of the RPL patients (plasma homocysteine and folate levels, natural killer cell number, platelet count, prothrombin time, and, activated partial thromboplastin time) were analyzed using multiple linear regression analyses.ResultsOur results suggest that weak associations between decreased RPL risk and the genotypes of miR-27a (AG and AG+GG), combination genotype of miR-27a/miR-423 (AG/GC), and haplotypes of miR-27a/miR-423/miR-449b/miR-605 (G-C-A-G) and miR-27a/miR-449b/miR-605 (G-A-G), whereas weak associations between increased RPL risk and genotypes of miR-449b (GG and AG+GG), combination genotypes of miR-423/miR-449b (CC/GG and CA/AG), miR-449b/miR-605 (AG/AG), haplotypes of miR-27a/miR-423/miR-449b/miR-605 (A-C-G-A, A-A-A-G, and G-C-G-G), miR-27a/miR-423/miR-449b (A-C-G), miR-27a/miR-449b/miR-605 (A-A-G, A-G-A, and G-G-G), miR-423/miR-449b/miR-605 (C-G-G and A-A-G), and miR-423/miR-449b (C-G and A-A). The genotypes of miR-27a (AG and AG+GG) also showed significant contributions to the prediction of folate levels in RPL patients.ConclusionsThe study showed associations between miRNA polymorphisms (miR-27a rs895819 and miR-449b rs10061133) and RPL development, and between the miRNA polymorphism (miR-27a rs895819) and plasma folate levels.

Project description:Study questionWhat is the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature?Summary answerThe guideline development group formulated 77 recommendations answering 18 key questions on investigations and treatments for RPL, and on how care should be organized.What is known alreadyA previous guideline for the investigation and medical treatment of recurrent miscarriage was published in 2006 and is in need of an update.Study design size durationThe guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 31 March 2017 and written in English were included. Cumulative live birth rate, live birth rate and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes.Participants/materials setting methodsBased on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee.Main results and the role of chanceThe guideline provides 38 recommendations on risk factors, prevention and investigations in couples with RPL, and 39 recommendations on treatments. These include 60 evidence-based recommendations - of which 31 were formulated as strong recommendations and 29 as conditional - and 17 good practice points. The evidence supporting investigations and treatment of couples with RPL is limited and of moderate quality. Of the evidence-based recommendations, only 10 (16.3%) were supported by moderate quality evidence. The remaining recommendations were supported by low (35 recommendations: 57.4%), or very low quality evidence (16 recommendations: 26.2%). There were no recommendations based on high quality evidence. Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions investigations and treatments that should not be used for couples with RPL.Limitations reasons for cautionSeveral investigations and treatments are offered to couples with RPL, but most of them are not well studied. For most of these investigations and treatments, a recommendation against the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised.Wider implications of the findingsThe guideline provides clinicians with clear advice on best practice in RPL, based on the best evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. One of the most important consequences of the limited evidence is the absence of evidence for a definition of RPL.Study funding/competing interestsThe guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. J.E. reports position funding from CARE Fertility. S.L. reports position funding from SpermComet Ltd. S.M. reports research grants, consulting and speaker's fees from GSK, BMS/Pfizer, Sanquin, Aspen, Bayer and Daiichi Sankyo. S.Q. reports speaker's fees from Ferring. The other authors report no conflicts of interest.ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.

Dataset Information

Analysis of genes coding for CD46, CD55, and C4b-binding protein in patients with idiopathic, recurrent, spontaneous pregnancy loss.

Publications

Analysis of genes coding for CD46, CD55, and C4b-binding protein in patients with idiopathic, recurrent, spontaneous pregnancy loss.

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