Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario

El aborto espontáneo recurrente (AER) se define como dos o más pérdidas consecutivas de la gestación antes de la semana 20 del desarrollo intrauterino. Esta patología afecta a aproximadamente entre el 1% y el 5% de las parejas. La etiología del AER se puede dividir en causas no-genéticas como genéti...

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Fecha de publicación:: 2018

Institución:: Universidad del Rosario

Repositorio:: Repositorio EdocUR - U. Rosario

Idioma:: spa

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oai_identifier_str	oai:repository.urosario.edu.co:10336/18933
network_acronym_str	EDOCUR2
network_name_str	Repositorio EdocUR - U. Rosario
repository_id_str
dc.title.spa.fl_str_mv	Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario
title	Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario
spellingShingle	Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario Pérdida recurrente de la gestación Falla de la implantación Genética Genómica Mutaciones FOXD1 Biomarcadores moleculares Ginecología & otras especialidades médicas Recurrent pregnancy loss Recurrent implantation failure Molecular biomarkers FOXD1 Genetics Genomics Mutations Aborto espontáneo Aborto habitual Genes Genética molecular
title_short	Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario
title_full	Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario
title_fullStr	Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario
title_full_unstemmed	Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario
title_sort	Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario
dc.contributor.advisor.none.fl_str_mv	Laissue, Paul
dc.subject.spa.fl_str_mv	Pérdida recurrente de la gestación Falla de la implantación Genética Genómica Mutaciones FOXD1 Biomarcadores moleculares
topic	Pérdida recurrente de la gestación Falla de la implantación Genética Genómica Mutaciones FOXD1 Biomarcadores moleculares Ginecología & otras especialidades médicas Recurrent pregnancy loss Recurrent implantation failure Molecular biomarkers FOXD1 Genetics Genomics Mutations Aborto espontáneo Aborto habitual Genes Genética molecular
dc.subject.ddc.spa.fl_str_mv	Ginecología & otras especialidades médicas
dc.subject.keyword.spa.fl_str_mv	Recurrent pregnancy loss Recurrent implantation failure Molecular biomarkers FOXD1 Genetics Genomics Mutations
dc.subject.lemb.spa.fl_str_mv	Aborto espontáneo Aborto habitual Genes Genética molecular
description	El aborto espontáneo recurrente (AER) se define como dos o más pérdidas consecutivas de la gestación antes de la semana 20 del desarrollo intrauterino. Esta patología afecta a aproximadamente entre el 1% y el 5% de las parejas. La etiología del AER se puede dividir en causas no-genéticas como genéticas. Sin embargo, ~50% de los casos se considera idiopático. De manera análoga, la etiología molecular de la falla de implantación recurrente (FIR), definida como la falla de la implantación en al menos 2 o más ciclos consecutivos de fertilización in vitro, es poco conocida. La etiología molecular del AER y de la FIR está asociada potencialmente a variantes de secuencia en cientos de genes candidato que participan en las cascadas moleculares fisiológicas de la implantación y durante toda la gestación. La aproximación gen candidato, usando la secuenciación de Sanger, ha sido de utilidad para la descripción de pocos genes implicados en el AER. La secuenciación de siguiente generación (NGS) ha sido una herramienta eficiente puesto que permite el estudio simultáneo de múltiples genes relacionados con enfermedades complejas. En la primera parte de este trabajo de tesis se utilizó la aproximación NGS-exoma para identificar nuevos genes y mutaciones potencialmente implicadas en el desarrollo del AER. Algunas de las mutaciones encontradas por este abordaje fueron estudiadas mediante ensayos funcionales in vitro para determinar su posible efecto deletéreo. La identificación de la variante THBD p.Trp153Gly en mujeres colombianas con AER y su validación mediante ensayos funcionales in vitro sugiere, por primera vez, una relación directa entre formas mutantes de esta proteína y la fisiopatología del AER, considerándose como un posible marcador molecular para el diagnóstico en pacientes colombianas con AER idiopático. En la segunda parte del presente trabajo de tesis identificamos y estudiamos funcionalmente nuevas mutaciones de FOXD1, un gen relevante en la fisiología endometrial y placentaria, identificadas en pacientes FIR, AER, preeclampsia (PE) y retardo del crecimiento intrauterino (RCIU). Los ensayos funcionales in vitro demostraron que las mutaciones FOXD1-p.His267Tyr y FOXD1-p.Arg57del. modifican la transactivación del promotor de C3, contribuyendo con el fenotipo. FOXD1 podría considerarse en consecuencia un marcador molecular diagnóstico para las pacientes con AER, FIR, RCIU y PE. Por último, ensayos por inmunoprecipitación de la cromatina secuenciación NGS (ChIP-seq) permitieron determinar potenciales nuevos genes blanco directos de FOXD1 (CTSC, CD86, CMA1 y TRPC6) en un contexto placentario. La información generada durante este trabajo de tesis aporta al conocimiento sobre el origen genético del AER, la FIR, y el RCIU/PE. Estos resultados podrían ser de utilidad para los especialistas clínicos en el contexto del desarrollo de la medicina traslacional.
publishDate	2018
dc.date.created.none.fl_str_mv	2018-12-03
dc.date.issued.none.fl_str_mv	2018
dc.date.accessioned.none.fl_str_mv	2019-01-28T13:20:53Z
dc.date.available.none.fl_str_mv	2019-01-28T13:20:53Z
dc.type.eng.fl_str_mv	doctoralThesis
dc.type.coar.fl_str_mv	http://purl.org/coar/resource_type/c_db06
dc.type.document.spa.fl_str_mv	Tesis
dc.type.spa.spa.fl_str_mv	Tesis de doctorado
dc.identifier.doi.none.fl_str_mv	https://doi.org/10.48713/10336_18933
dc.identifier.uri.none.fl_str_mv	http://repository.urosario.edu.co/handle/10336/18933
url	https://doi.org/10.48713/10336_18933 http://repository.urosario.edu.co/handle/10336/18933
dc.language.iso.none.fl_str_mv	spa
language	spa
dc.rights.spa.fl_str_mv	Atribución-NoComercial-SinDerivadas 2.5 Colombia
dc.rights.coar.fl_str_mv	http://purl.org/coar/access_right/c_abf2
dc.rights.acceso.spa.fl_str_mv	Abierto (Texto Completo)
dc.rights.uri.none.fl_str_mv	http://creativecommons.org/licenses/by-nc-nd/2.5/co/
rights_invalid_str_mv	Atribución-NoComercial-SinDerivadas 2.5 Colombia Abierto (Texto Completo) http://creativecommons.org/licenses/by-nc-nd/2.5/co/ http://purl.org/coar/access_right/c_abf2
dc.format.mimetype.none.fl_str_mv	application/pdf
dc.publisher.spa.fl_str_mv	Universidad del Rosario
dc.publisher.department.spa.fl_str_mv	Facultad de Ciencias Naturales y Matemáticas
dc.publisher.program.spa.fl_str_mv	Doctorado en Ciencias Biomédicas
institution	Universidad del Rosario
dc.source.bibliographicCitation.spa.fl_str_mv	Li, T. C. et al. Recurrent miscarriage: aetiology, management and prognosis. Hum. Reprod. Update 8, 463–81 (2002). Rai, R. & Regan, L. Recurrent miscarriage. Lancet 368, 601–611 (2006). Stirrat, G. M. Recurrent miscarriage. Lancet 336, 673–675 (1990). Hogge, W. A., Byrnes, A. L., Lanasa, M. C. & Surti, U. The clinical use of karyotyping spontaneous abortions. Am. J. Obstet. Gynecol. 189, 397-400; discussion 400–2 (2003). Bricker Leanne & Farquharson Roy G. Recurring miscarriage. Obstet. Gynaecol. 2, 17–23 (2000). Rai, R. S., Clifford, K., Cohen, H. & Regan, L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum. Reprod. 10, 3301–3304 (1995). Santos, T. da S. et al. Antiphospholipid syndrome and recurrent miscarriage: A systematic review and meta-analysis. J. Reprod. Immunol. 123, 78–87 (2017). Mak, I. Y. H. et al. Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro. J. Clin. Endocrinol. Metab. 87, 2581–2588 (2002). Bose, P. et al. Heparin and aspirin attenuate placental apoptosis in vitro: Implications for early pregnancy failure. Am. J. Obstet. Gynecol. 192, 23–30 (2005). Salim, R., Regan, L., Woelfer, B., Backos, M. & Jurkovic, D. A comparative study of the morphology of congenital uterine anomalies in women with and without a history of recurrent first trimester miscarriage. Hum. Reprod. (2003). doi:10.1093/humrep/deg030 Grimbizis, G. F., Camus, M., Tarlatzis, B. C., Bontis, J. N. & Devroey, P. Clinical implications of uterine malformations and hysteroscopic treatment results. Human Reproduction Update 7, 161–174 (2001). Hart, R. et al. A prospective controlled study of the effect of intramural uterine fibroids on the outcome of assisted conception. Human reproduction (Oxford, England) 16, (2001). Rackow, B. W. & Taylor, H. S. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil. Steril. 93, 2027–2034 (2010). Hirahara, F. et al. Hyperprolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trials. Fertil. Steril. 70, 246–252 (1998). Garzia, E. et al. Lack of expression of endometrial prolactin in early implantation failure: A pilot study. Hum. Reprod. 19, 1911–1916 (2004). Craig, L. B., Ke, R. W. & Kutteh, W. H. Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss. Fertil. Steril. 78, 487–490 (2002). Rai, R., Backos, M., Rushworth, F. & Regan, L. Polycystic ovaries and recurrent miscarriage--a reappraisal. Hum. Reprod. 15, 612–615 (2000). Kaur, R. & Gupta, K. Endocrine dysfunction and recurrent spontaneous abortion: An overview. Int. J. Appl. Basic Med. Res. 6, 79 (2016). Clifford, K., Flanagan, A. M. & Regan, L. Endometrial CD56+ natural killer cells in women with recurrent miscarriage: a histomorphometric study. Hum. Reprod. 14, 2727–2730 (1999). Reinhard, G., Noll, A., Schlebusch, H., Mallmann, P. & Ruecker, A. Shifts in the TH1/TH2 balance during human pregnancy correlate with apoptotic changes. Biochem. Biophys. Res. Commun. 245, 933–938 (1998). Beaman, K. D. et al. Immune Etiology of Recurrent Pregnancy Loss and Its Diagnosis. Am. J. Reprod. Immunol. 67, 319–325 (2012). Ralph, S. G., Rutherford, A. J. & Wilson, J. D. Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study. BMJ 319, 220–223 (1999). Hay, P. E. et al. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 308, 295–298 (1994). Isik, G., Demirezen, Ş., Dönmez, H. & Beksaç, M. Bacterial vaginosis in association with spontaneous abortion and recurrent pregnancy losses. J. Cytol. 33, 135 (2016). Giakoumelou, S. et al. The role of infection in miscarriage. Hum. Reprod. Update 22, 116–133 (2016). Jia, C.-W. et al. Aneuploidy in Early Miscarriage and its Related Factors. Chin. Med. J. (Engl). 128, 2772 (2015). Hyde, K. J. & Schust, D. J. Genetic Considerations in Recurrent Pregnancy Loss. Cold Spring Harb. Perspect. Med. 5, a023119–a023119 (2015). Sierra S & Stephenson M. Genetics of recurrent pregnancy loss. Semin Reprod Med. 24, 17–24. (2006). Stephenson, M. D., Awartani, K. A. & Robinson, W. P. Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study. Hum. Reprod. (2002). doi:10.1016/S0015-0282(01)02285-3 Hassold, T. & Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nat. Rev. Genet. 2, 280–291 (2001). Rubio, C. et al. Chromosomal abnormalities and embryo development in recurrent miscarriage couples. Hum. Reprod. (2003). doi:10.1093/humrep/deg015 Choi, T. Y., Lee, H. M., Park, W. K., Jeong, S. Y. & Moon, H. S. Spontaneous abortion and recurrent miscarriage: A comparison of cytogenetic diagnosis in 250 cases. Obstet. Gynecol. Sci. 57, 518 (2014). Coelho, F. F. et al. Detection of aneuploidies in spontaneous abortions by quantitative fluorescent PCR with short tandem repeat markers: a retrospective study. Genet. Mol. Res. 15, (2016). ESHRE Capri Workshop Group. Genetic aspects of female reproduction. Hum. Reprod. Update 14, 293–307. (2008). Menasha, J., Levy, B., Hirschhorn, K. & Kardon, N. B. Incidence and spectrum of chromosome abnormalities in spontaneous abortions: New insights from a 12-year study. Genet. Med. 7, 251–263 (2005). Uehara, S. et al. Preferential X-chromosome inactivation in women with idiopathic recurrent pregnancy loss. in Fertility and Sterility 76, 908–914 (2001). Sangha, K. K., Stephenson, M. D., Brown, C. J. & Robinson, W. P. Extremely skewed X-chromosome inactivation is increased in women with recurrent spontaneous abortion. American journal of human genetics 65, 913–917 (1999). Aldrich, C. L. et al. HLA-G genotypes and pregnancy outcome in couples with unexplained recurrent miscarriage. Molecular human reproduction 7, (2001). Pfeiffer, K. A., Fimmers, R., Engels, G., van der Ven, H. & van der Ven, K. The HLA-G genotype is potentially associated with idiopathic recurrent spontaneous abortion. Mol. Hum. Reprod. 7, 373–8 (2001). Kovalevsky, G., Gracia, C. R., Berlin, J. A., Sammel, M. D. & Barnhart, K. T. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch. Intern. Med. 164, 558–563 (2004). Rey, E., Kahn, S. R., David, M. & Shrier, I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet (London, England) 361, 901–8 (2003). Rai, R., Backos, M., Elgaddal, S., Shlebak, A. & Regan, L. Factor V Leiden and recurrent miscarriage-prospective outcome of untreated pregnancies. Hum. Reprod. 17, 442–445 (2002). Laissue, P. et al. Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans. Open Biol. 6, 160109 (2016). Polanski, L. T. et al. What exactly do we mean by ‘recurrent implantation failure’? A systematic review and opinion. Reprod. Biomed. Online 28, 409–423 (2014). Croucher, C. A., Lass, A., Margara, R. & Winston, R. M. Predictive value of the results of a first in-vitro fertilization cycle on the outcome of subsequent cycles. Hum. Reprod. 13, 403–8 (1998). Yang, R. et al. Biochemical pregnancy and spontaneous abortion in first IVF cycles are negative predictors for subsequent cycles: an over 10,000 cases cohort study. Arch. Gynecol. Obstet. 292, 453–458 (2015). Simon, A. & Laufer, N. Assessment and treatment of repeated implantation failure (RIF). J. Assist. Reprod. Genet. 29, 1227–1239 (2012). Rinehart, J. Recurrent implantation failure: Definition. J. Assist. Reprod. Genet. 24, 284–287 (2007). Timeva, T., Shterev, A. & Kyurkchiev, S. Recurrent implantation failure: The role of the endometrium. J. Reprod. Infertil. 15, 173–183 (2014). Simon, A. & Laufer, N. Repeated implantation failure: Clinical approach. Fertil. Steril. 97, 1039–1043 (2012). El-Toukhy, T. & Taranissi, M. Towards better quality research in recurrent implantation failure: standardizing its definition is the first step. Reprod. Biomed. Online 12, 383–5 (2006). Levi Setti, P. E. et al. Implantation failure in assisted reproduction technology and a critical approach to treatment. Ann. N. Y. Acad. Sci. 1034, 184–199 (2004). Ocal, P. et al. Recurrent implantation failure is more frequently seen in female patients with poor prognosis. Int. J. Fertil. Steril. 6, 71–8 (2012). Regan, L., Braude, P. R. & Trembath, P. L. Influence of past reproductive performance on risk of spontaneous abortion. BMJ 299, 541–545 (1989). Knudsen, U. B., Hansen, V., Juul, S. & Secher, N. J. Prognosis of a new pregnancy following previous spontaneous abortions. Eur. J. Obstet. Gynecol. Reprod. Biol. 39, 31–36 (1991). Strobino, B. et al. Characteristics of women with recurrent spontaneous abortions and women with favorable reproductive histories. Am. J. Public Health 76, 986–91 (1986). Kolte, A. M. M. et al. A genome-wide scan in affected sibling pairs with idiopathic recurrent miscarriage suggests genetic linkage. MHR Basic Sci. Reprod. Med. 17, 379–385 (2011). Shekouhi, S. et al. Identification of Xq22.1-23 as a region linked with hereditary recurrent spontaneous abortion in a family. Iran. J. Reprod. Med. 11, 659–64 (2013). Li Wang, Zeng Chan Wang, Cui Xie, Xiao Feng Liu & Mao Sheng Yang. Genome-Wide Screening for Risk Loci of Idiopathic Recurrent Miscarriage in a Han Chinese Population: A Pilot Study. Reprod. Sci. 17, 578–584 (2010). Kaare, M. et al. Variations in the thrombomodulin and endothelial protein C receptor genes in couples with recurrent miscarriage. Hum. Reprod. 22, 864–8 (2007). Mercier, E., Lissalde-Lavigne, G. & Gris, J.-C. JAK2 V617F Mutation in Unexplained Loss of First Pregnancy. N. Engl. J. Med. 357, 1984–1985 (2007). Kaare, M., Painter, J. N., Ulander, V. M., Kaaja, R. & Aittomäki, K. Variations of the amnionless gene in recurrent spontaneous abortions. Mol. Hum. Reprod. 12, 25–29 (2006). Neveling, K. et al. A Post-Hoc Comparison of the Utility of Sanger Sequencing and Exome Sequencing for the Diagnosis of Heterogeneous Diseases. Hum. Mutat. 34, 1721–1726 (2013). Baudhuin, L. M. et al. Confirming Variants in Next-Generation Sequencing Panel Testing by Sanger Sequencing. J. Mol. Diagnostics 17, 456–461 (2015). Laissue, P. Aetiological coding sequence variants in non-syndromic premature ovarian failure: From genetic linkage analysis to next generation sequencing. Mol. Cell. Endocrinol. 411, 243–257 (2015). Lee, K. Y. & DeMayo, F. J. Animal models of implantation. Reproduction 128, 679–695 (2004). Wilcox, A. J., Baird, D. D. & Weinberg, C. R. Time of Implantation of the Conceptus and Loss of Pregnancy. N. Engl. J. Med. 340, 1796–1799 (1999). Wimsatt, W. A. Some comparative aspects of implantation. Biol. Reprod. 12, 1–40 (1975). Aghajanova, L. et al. Comparative Transcriptome Analysis of Human Trophectoderm and Embryonic Stem Cell-Derived Trophoblasts Reveal Key Participants in Early Implantation. Biol. Reprod. 86, 1–21 (2012). Cha, J., Sun, X. & Dey, S. K. Mechanisms of implantation: strategies for successful pregnancy. Nat. Med. 18, 1754–1767 (2012). King, A. Uterine leukocytes and decidualization. Hum. Reprod. Update 6, 28–36 (2000). Christian, M. et al. Interferon-gamma modulates prolactin and tissue factor expression in differentiating human endometrial stromal cells. Endocrinology 142, 3142–51 (2001). Irwin, J. C. & Giudice, L. C. Insulin-like growth factor binding protein-1 binds to placental cytotrophoblast alpha5beta1 integrin and inhibits cytotrophoblast invasion into decidualized endometrial stromal cultures. Growth Horm. IGF Res. 8, 21–31 (1998). Kusama, K., Yoshie, M., Tamura, K., Imakawa, K. & Tachikawa, E. EPAC2-mediated calreticulin regulates LIF and COX2 expression in human endometrial glandular cells. J. Mol. Endocrinol. 54, 17–24 (2014). Li, Q. et al. WNT4 Acts Downstream of BMP2 and Functions via β-Catenin Signaling Pathway to Regulate Human Endometrial Stromal Cell Differentiation. Endocrinology 154, 446–457 (2013). Aghajanova, L. Leukemia inhibitory factor and human embryo implantation. Ann N Y Acad Sci 1034, 176–183 (2004). Kojima, K. et al. Expression of leukaemia inhibitory factor (LIF) receptor in human placenta: a possible role for LIF in the growth and differentiation of trophoblasts. Hum. Reprod. 10, 1907–11 (1995). Carson, D. D. et al. Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening. Mol. Hum. Reprod. 8, 871–879 (2002). Kao, L. C. et al. Global gene profiling in human endometrium during the window of implantation. Endocrinology 143, 2119–2138 (2002). Popovici, R. M., Kao, L. C. & Giudice, L. C. Discovery of new inducible genes in in vitro decidualized human endometrial stromal cells using microarray technology. Endocrinology 141, 3510–3513 (2000). Uegaki, K. et al. PTEN is involved in the signal transduction pathway of contact inhibition in endometrial cells. Cell Tissue Res. 323, 523–528 (2006). Ejskjaer, K. et al. Expression of the epidermal growth factor system in human endometrium during the menstrual cycle. Mol. Hum. Reprod. 11, 543–551 (2005). Kats, R., Al-Akoum, M., Guay, S., Metz, C. & Akoum, A. Cycle-dependent expression of macrophage migration inhibitory factor in the human endometrium. Hum. Reprod. 20, 3518–3525 (2005). Print, C. et al. Soluble factors from human endometrium promote angiogenesis and regulate the endothelial cell transcriptome. Hum. Reprod. 19, 2356–2366 (2004). Stavreus-Evers, A. et al. Co-existence of heparin-binding epidermal growth factor-like growth factor and pinopodes in human endometrium at the time of implantation. Mol. Hum. Reprod. 8, 765–769 (2002). Nikas, G. & Aghajanova, L. Endometrial pinopodes: some more understanding on human implantation? Reprod. Biomed. Online 4 Suppl 3, 18–23 (2002). Jones, R. L., Stoikos, C., Findlay, J. K. & Salamonsen, L. A. TGF-?? superfamily expression and actions in the endometrium and placenta. Reproduction (2006). doi:10.1530/rep.1.01076 Li, Y.-H., Kuo, C.-H., Shi, G.-Y. & Wu, H.-L. The role of thrombomodulin lectin-like domain in inflammation. J. Biomed. Sci. 19, 34 (2012). Conway, E. M. et al. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. J. Exp. Med. 196, 565–77 (2002). Van Dreden, P., Woodhams, B., Rousseau, A., Favier, M. & Favier, R. Comparative evaluation of Tissue factor and Thrombomodulin activity changes during normal and idiopathic early and late foetal loss: The cause of hypercoagulability? Thromb. Res. 129, 787–792 (2012). Isermann, B. et al. The thrombomodulin–protein C system is essential for the maintenance of pregnancy. Nat. Med. 9, 331–337 (2003). Griesshammer, M., Struve, S. & Harrison, C. M. Essential thrombocythemia/polycythemia vera and pregnancy: The need for an observational study in Europe. Semin. Thromb. Hemost. 32, 422–429 (2006). Kralovics, R. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–90 (2005). Melillo, L. et al. Outcome of 122 pregnancies in essential thrombocythemia patients: A report from the Italian registry. Am. J. Hematol. 84, 636–640 (2009). Passamonti, F. et al. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation. Blood 110, 485–9 (2007). Barber, L. J. et al. Comprehensive genomic analysis of a BRCA2 deficient human pancreatic cancer. PLoS One (2011). doi:10.1371/journal.pone.0021639 Laissue, P. The molecular complexity of primary ovarian insufficiency aetiology and the use of massively parallel sequencing. Mol. Cell. Endocrinol. 460, 170–180 (2018). Çalişkan, M. et al. Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13. Hum. Mol. Genet. (2011). doi:10.1093/hmg/ddq569 Veltman, J. A. & Brunner, H. G. De novo mutations in human genetic disease. Nature Reviews Genetics (2012). doi:10.1038/nrg3241 Hrdlickova, B., de Almeida, R. C., Borek, Z. & Withoff, S. Genetic variation in the non-coding genome: Involvement of micro-RNAs and long non-coding RNAs in disease. Biochim. Biophys. Acta - Mol. Basis Dis. 1842, 1910–1922 (2014). Huang, Q. Genetic Study of Complex Diseases in the Post-GWAS Era. J. Genet. Genomics 42, 87–98 (2015). Gibson, G. Rare and common variants: twenty arguments. Nat. Rev. Genet. 13, 135–145 (2012). Lettre, G. Rare and low-frequency variants in human common diseases and other complex traits. J. Med. Genet. 51, 705–14 (2014). Zuk, O. et al. Searching for missing heritability: Designing rare variant association studies. Proc. Natl. Acad. Sci. 111, E455–E464 (2014). Mitropoulos, K. et al. Success stories in genomic medicine from resource-limited countries. Hum. Genomics 9, 11 (2015). Fonseca, D. J. et al. Next generation sequencing in women affected by nonsyndromic premature ovarian failure displays new potential causative genes and mutations. Fertil. Steril. 104, 154–62.e2 (2015). Patiño, L. C. et al. Exome Sequencing Is an Efficient Tool for Variant Late-Infantile Neuronal Ceroid Lipofuscinosis Molecular Diagnosis. PLoS One 9, e109576 (2014). Ortega-Recalde, O. et al. Whole-Exome Sequencing Enables Rapid Determination of Xeroderma Pigmentosum Molecular Etiology. PLoS One 8, e64692 (2013). Diggle, C. P. et al. Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis. Hum. Mutat. 33, 1175–1181 (2012). Patiño, L. C. et al. New mutations in non-syndromic primary ovarian insufficiency patients identified via whole-exome sequencing. Hum. Reprod. 32, 1512–1520 (2017). Carlosama, C. et al. A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency. Hum. Mol. Genet. 26, 3161–3166 (2017). Qiao, Y. et al. Whole exome sequencing in recurrent early pregnancy loss. Mol. Hum. Reprod. 22, 364–72 (2016). Sõber, S. et al. RNA sequencing of chorionic villi from recurrent pregnancy loss patients reveals impaired function of basic nuclear and cellular machinery. Sci. Rep. 6, 38439 (2016). Wang, J. mei et al. Deep-sequencing identification of differentially expressed miRNAs in decidua and villus of recurrent miscarriage patients. Arch. Gynecol. Obstet. 293, 1125–1135 (2016). Quintero-Ronderos, P. et al. Novel genes and mutations in patients affected by recurrent pregnancy loss. PLoS One 12, e0186149 (2017). Lissalde-Lavigne, G. et al. Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case-control ‘NOHA first’ study. J. Thromb. Haemost. 3, 2178–84 (2005). Wang, Q., Shashikant, C. S., Jensen, M., Altman, N. S. & Girirajan, S. Novel metrics to measure coverage in whole exome sequencing datasets reveal local and global non-uniformity. Sci. Rep. 7, 885 (2017). Lee, S. M., Wu, B. & Kersey, J. H. Likelihood-Based Approach to Gene Set Enrichment Analysis with a Finite Mixture Model. Stat. Biosci. 6, 38–54 (2014). Heifetz, A. et al. The Fragment Molecular Orbital Method Reveals New Insight into the Chemical Nature of GPCR–Ligand Interactions. J. Chem. Inf. Model. 56, 159–172 (2016). Fedorov, D. G., Nagata, T. & Kitaura, K. Exploring chemistry with the fragment molecular orbital method. Phys. Chem. Chem. Phys. 14, 7562 (2012). Stewart, J. J. MOPAC: a semiempirical molecular orbital program. J. Comput. Aided. Mol. Des. 4, 1–105 (1990). Hitaoka, S., Chuman, H. & Yoshizawa, K. A QSAR study on the inhibition mechanism of matrix metalloproteinase-12 by arylsulfone analogs based on molecular orbital calculations. Org. Biomol. Chem. 13, 793–806 (2015). Rozen, S. & Skaletsky, H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol. Biol. 132, 365–86 (2000). Hu, Z. et al. Structural Insights into the pH-Dependent Conformational Change and Collagen Recognition of the Human Mannose Receptor. Structure 26, 60–71.e3 (2018) Roy, A., Kucukural, A. & Zhang, Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nat. Protoc. 5, 725–738 (2010). Zhang, Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics 9, 40 (2008). Yang, J. et al. The I-TASSER Suite: protein structure and function prediction. Nat. Methods 12, 7–8 (2015). Pettersen, E. F. et al. UCSF Chimera?A visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004). Dunbrack, R. L. Rotamer libraries in the 21st century. Curr. Opin. Struct. Biol. 12, 431–40 (2002). Phillips, J. C. et al. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781–1802 (2005). Huang, J. & MacKerell, A. D. CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data. J. Comput. Chem. 34, 2135–2145 (2013). Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. & Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926–935 (1983). Benkert, P., Biasini, M. & Schwede, T. Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics 27, 343–350 (2011). Chen, V. B. et al. MolProbity : all-atom structure validation for macromolecular crystallography. Acta Crystallogr. Sect. D Biol. Crystallogr. 66, 12–21 (2010). Humphrey, W., Dalke, A. & Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph. 14, 33–38 (1996). Voss, N. R. & Gerstein, M. 3V: cavity, channel and cleft volume calculator and extractor. Nucleic Acids Res. 38, W555–W562 (2010). Søndergaard, C. R., Olsson, M. H. M., Rostkowski, M. & Jensen, J. H. Improved Treatment of Ligands and Coupling Effects in Empirical Calculation and Rationalization of p K a Values. J. Chem. Theory Comput. 7, 2284–2295 (2011). Baker, N. A., Sept, D., Joseph, S., Holst, M. J. & McCammon, J. A. Electrostatics of nanosystems: Application to microtubules and the ribosome. Proc. Natl. Acad. Sci. 98, 10037–10041 (2001). Dolinsky, T. J., Nielsen, J. E., McCammon, J. A. & Baker, N. A. PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations. Nucleic Acids Res. 32, W665–W667 (2004). Sims, D., Sudbery, I., Ilott, N. E., Heger, A. & Ponting, C. P. Sequencing depth and coverage: key considerations in genomic analyses. Nat. Rev. Genet. 15, 121–132 (2014). Meynert, A. M., Ansari, M., FitzPatrick, D. R. & Taylor, M. S. Variant detection sensitivity and biases in whole genome and exome sequencing. BMC Bioinformatics 15, 247 (2014). Kim, K. et al. Effect of Next-Generation Exome Sequencing Depth for Discovery of Diagnostic Variants. Genomics Inform. 13, 31 (2015). Kiezun, A. et al. Exome sequencing and the genetic basis of complex traits. Nat. Genet. 44, 623–630 (2012) Goldstein, D. B. et al. Sequencing studies in human genetics: Design and interpretation. Nat. Rev. Genet. 14, 460–470 (2013). Tennessen, J. A. et al. Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes. Sci. (New York, NY) 337, 64–69 (2012). O’Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012). Delcour, C. et al. ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure. Genet. Med. (2018). doi:10.1038/s41436-018-0287-y Thusberg, J., Olatubosun, A. & Vihinen, M. Performance of mutation pathogenicity prediction methods on missense variants. Hum. Mutat. 32, 358–368 (2011). Walters-Sen, L. C. et al. Variability in pathogenicity prediction programs: impact on clinical diagnostics. Mol. Genet. Genomic Med. 3, 99–110 (2015). Dawood, F., Mountford, R., Farquharson, R. & Quenby, S. Genetic polymorphisms on the factor V gene in women with recurrent miscarriage and acquired APCR. Hum. Reprod. 22, 2546–2553 (2007). Altintas, A. et al. Factor V Leiden and G20210A prothrombin mutations in patients with recurrent pregnancy loss: data from the southeast of Turkey. Ann. Hematol. 86, 727–731 (2007). Aytekin, E., Ergun, S. G., Ergun, M. A. & Percin, F. E. Evaluation of GenoFlow Thrombophilia Array Test Kit in Its Detection of Mutations in Factor V Leiden (G1691A), Prothrombin G20210A, MTHFR C677T and A1298C in Blood Samples from 113 Turkish Female Patients. Genet. Test. Mol. Biomarkers 18, 717–721 (2014). Asselta, R., Tenchini, M. L. & Duga, S. Inherited defects of coagulation factor V: the hemorrhagic side. J. Thromb. Haemost. 4, 26–34 (2006). Steen, M. & Dahlbäck, B. Thrombin-mediated proteolysis of factor V resulting in gradual B-domain release and exposure of the factor Xa-binding site. J. Biol. Chem. 277, 38424–30 (2002). Erdogan, E., Bukys, M. A. & Kalafatis, M. The contribution of amino acid residues 1508-1515 of factor V to light chain generation. J. Thromb. Haemost. 6, 118–24 (2008). Peng, W., Quinn-Allen, M. A. & Kane, W. H. Mutation of hydrophobic residues in the factor Va C1 and C2 domains blocks membrane-dependent prothrombin activation. J. Thromb. Haemost. 3, 351–4 (2005). Otto, P. & Ladik, J. Investigation of the interaction between molecules at medium distances. Chem. Phys. 8, 192–200 (1975). Fiedler, Benjamin & Friedrich, Joachim. (2017). The incremental method - Theory and applications in chemistry and physics. 13. 132-190. 10.1039/9781782626862-00132. Xie, W. & Gao, J. Design of a Next Generation Force Field: The X-POL Potential. J. Chem. Theory Comput. 3, 1890–1900 (2007). Batra, J. et al. Matrix Metalloproteinase-10 (MMP-10) Interaction with Tissue Inhibitors of Metalloproteinases TIMP-1 and TIMP-2: BINDING STUDIES AND CRYSTAL STRUCTURE. J. Biol. Chem. 287, 15935–15946 (2012). Maruyama, I., Bell, C. E. & Majerus, P. W. Thrombomodulin is found on endothelium of arteries, veins, capillaries, and lymphatics, and on syncytiotrophoblast of human placenta. J. Cell Biol. 101, 363–71 (1985). Martin, F. A., Murphy, R. P. & Cummins, P. M. Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects. Am. J. Physiol. Heart Circ. Physiol. 304, H1585-97 (2013). Masini, S. et al. Thrombin-activatable fibrinolysis inhibitor polymorphisms and recurrent pregnancy loss. Fertil. Steril. 92, 694–702 (2009). Ito, T., Kakihana, Y. & Maruyama, I. Thrombomodulin as an intravascular safeguard against inflammatory and thrombotic diseases. Expert Opin. Ther. Targets 20, 151–158 (2016). Delvaeye, M. et al. Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome. N. Engl. J. Med. 361, 345–357 (2009). Huang, H.-C. et al. Thrombomodulin-mediated cell adhesion: involvement of its lectin-like domain. J. Biol. Chem. 278, 46750–9 (2003). Stortoni, P. et al. Placental thrombomodulin expression in recurrent miscarriage. Reprod. Biol. Endocrinol. 8, 1 (2010). Suzuki, K. et al. A domain composed of epidermal growth factor-like structures of human thrombomodulin is essential for thrombin binding and for protein C activation. J. Biol. Chem. 264, 4872–4876 (1989). Sood, R. et al. Maternal Par4 and platelets contribute to defective placenta formation in mouse embryos lacking thrombomodulin. Blood 112, 585–91 (2008). de Saint Martin, L. et al. Increased thrombin generation measured in the presence of thrombomodulin in women with early pregnancy loss. Fertil. Steril. 95, 1813–5.e1 (2011). Li, Y.-H., Shi, G.-Y. & Wu, H.-L. The role of thrombomodulin in atherosclerosis: from bench to bedside. Cardiovasc. Hematol. Agents Med. Chem. 4, 183–7 (2006). Parodi, A., Cummings, R. D. & Aebi, M. in Essentials of Glycobiology 3rd Editio, (2017). Suzuki, K. et al. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. EMBO J. 6, 1891–7 (1987). Ito, T. et al. Proteolytic Cleavage of High Mobility Group Box 1 Protein by Thrombin-Thrombomodulin Complexes. Arterioscler. Thromb. Vasc. Biol. 28, 1825–1830 (2008). Abeyama, K. et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J. Clin. Invest. 115, 1267–1274 (2005). Rossini, A. et al. HMGB1-stimulated human primary cardiac fibroblasts exert a paracrine action on human and murine cardiac stem cells. J. Mol. Cell. Cardiol. 44, 683–693 (2008). Yoshihara-Hirata, C. et al. Anti-HMGB1 Neutralizing Antibody Attenuates Periodontal Inflammation and Bone Resorption in a Murine Periodontitis Model. Infect. Immun. 86, (2018). Alsousi, A. A. & Igwe, O. J. Redox-active trace metal-induced release of high mobility group box 1(HMGB1) and inflammatory cytokines in fibroblast-like synovial cells is Toll-like receptor 4 (TLR4) dependent. Biochim. Biophys. Acta - Mol. Basis Dis. 1864, 3847–3858 (2018) Shirasuna, K. et al. AGEs and HMGB1 Increase Inflammatory Cytokine Production from Human Placental Cells, Resulting in an Enhancement of Monocyte Migration. Am. J. Reprod. Immunol. 75, 557–568 (2016). Amin, A. R. & Islam, A. B. M. M. K. Genomic Analysis and Differential Expression of HMG and S100A Family in Human Arthritis: Upregulated Expression of Chemokines, IL-8 and Nitric Oxide by HMGB1. DNA Cell Biol. 33, 550–565 (2014) Huang, Q. T. et al. Advanced glycation end products as an upstream molecule triggers ROS-induced sFlt-1 production in extravillous trophoblasts: A novel bridge between oxidative stress and preeclampsia. Placenta 34, 1177–1182 (2013). Min, H. J. et al. ROS-dependent HMGB1 secretion upregulates IL-8 in upper airway epithelial cells under hypoxic condition. Mucosal Immunol. 10, 685–694 (2017). Sagheddu, R. et al. Targeting RAGE as a potential therapeutic approach to Duchenne muscular dystrophy. Hum. Mol. Genet. 27, 3734–3746 (2018). Patel, V. et al. The stretch responsive microRNA miR-148a-3p is a novel repressor of IKBKB, NF- κ B signaling, and inflammatory gene expression in human aortic valve cells. FASEB J. 29, 1859–1868 (2015). Anjana, R. et al. Aromatic-aromatic interactions in structures of proteins and protein-DNA complexes: a study based on orientation and distance. Bioinformation 8, 1220–1224 (2012). Bignucolo, O., Leung, H. T. A., Grzesiek, S. & Bernèche, S. Backbone Hydration Determines the Folding Signature of Amino Acid Residues. J. Am. Chem. Soc. 137, 4300–4303 (2015) Zhang, Z., Witham, S. & Alexov, E. On the role of electrostatics in protein–protein interactions. Phys. Biol. 8, 035001 (2011). Andersson, U. et al. High Mobility Group 1 Protein (Hmg-1) Stimulates Proinflammatory Cytokine Synthesis in Human Monocytes. J. Exp. Med. 192, 565–570 (2000). Bhutada, S. et al. High mobility group box 1 (HMGB1) protein in human uterine fluid and its relevance in implantation. Hum. Reprod. 29, 763–780 (2014). Riesewijk, A. et al. Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology. Mol. Hum. Reprod. 9, 253–64 (2003). Kwak-Kim, J. Y. H., Gilman-Sachs, A. & Kim, C. E. in Immunology of Gametes and Embryo Implantation 64–79 (KARGER, 2005). doi:10.1159/000087821 Bates, M. D., Quenby, S., Takakuwa, K., Johnson, P. M. & Vince, G. S. Aberrant cytokine production by peripheral blood mononuclear cells in recurrent pregnancy loss? Hum. Reprod. 17, 2439–44 (2002). Tian, H., McKnight, S. L. & Russell, D. W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11, 72–82 (1997). Takeda, N. et al. Endothelial PAS domain protein 1 gene promotes angiogenesis through the transactivation of both vascular endothelial growth factor and its receptor, Flt-1. Circ. Res. 95, 146–53 (2004). Maemura, K. et al. Generation of a dominant-negative mutant of endothelial PAS domain protein 1 by deletion of a potent C-terminal transactivation domain. J. Biol. Chem. 274, 31565–70 (1999). Depoix, C. L. L., de Selliers, I., Hubinont, C. & Debieve, F. HIF1A and EPAS1 potentiate hypoxia-induced upregulation of inhibin alpha chain expression in human term cytotrophoblasts in vitro. Mol. Hum. Reprod. 23, gax002 (2017). L’Hôte, D. et al. Centimorgan-range one-step mapping of fertility traits using interspecific recombinant congenic mice. Genetics 176, 1907–21 (2007). Laissue, P., L’Hôte, D., Serres, C. & Vaiman, D. Mouse models for identifying genes modulating fertility parameters. animal 3, 55 (2009). Laissue, P. et al. Identification of Quantitative Trait Loci responsible for embryonic lethality in mice assessed by ultrasonography. Int. J. Dev. Biol. 53, 623–629 (2009). Quintero-Ronderos, P. et al. THBD sequence variants potentially related to recurrent pregnancy loss. Reprod. Biol. Endocrinol. 15, 92 (2017). Vatin, M. et al. Refined Mapping of a Quantitative Trait Locus on Chromosome 1 Responsible for Mouse Embryonic Death. PLoS One 7, e43356 (2012). Vatin, M. et al. Polymorphisms of human placental alkaline phosphatase are associated with in vitro fertilization success and recurrent pregnancy loss. Am. J. Pathol. 184, 362–368 (2014). L’Hôte, D. et al. Interspecific resources: a major tool for quantitative trait locus cloning and speciation research. BioEssays 32, 132–42 (2010). Guénet, J. L. & Bonhomme, F. Wild mice: an ever-increasing contribution to a popular mammalian model. Trends Genet. 19, 24–31 (2003). Burgio, G. et al. Interspecific Recombinant Congenic Strains Between C57BL/6 and Mice of the Mus spretus Species: A Powerful Tool to Dissect Genetic Control of Complex Traits. Genetics 177, 2321–33 (2007). Quintero-Ronderos, P. & Laissue, P. The multisystemic functions of FOXD1 in development and disease. J. Mol. Med. 96, 725–739 (2018). Feng, J., Liu, T., Qin, B., Zhang, Y. & Liu, X. S. Identifying ChIP-seq enrichment using MACS. Nat. Protoc. 7, 1728–1740 (2012). Zhang, Y. et al. Model-based Analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008). Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012). Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009). ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012). Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010). He, Q., Johnston, J. & Zeitlinger, J. ChIP-nexus enables improved detection of in vivo transcription factor binding footprints. Nat. Biotechnol. 33, 395–401 (2015). Welch, R. P. et al. Chipenrich: Gene Set Enrichment For ChIP-seq Peak Data. (2017). at <https://bioconductor.org/packages/devel/bioc/vignettes/chipenrich/inst/doc/chipenrich-vignette.html> Liu, T. MACS2 pileup value in xls file. (2014). at <https://groups.google.com/d/msg/macs-announcement/c__KCotHsok/Wp1VdX3XgAUJ> Elemento, O. & Giannopoulou, E. G. ChIP sequencing analysis in R/Bioconductor. (2014). at <http://physiology.med.cornell.edu/faculty/elemento/lab/data/courses/2014/CSHLseq/ChIP-seq.pdf> Sahu, P. Biostars: Bioinformatics explained. (2015). at <https://www.biostars.org/p/198970/#210571> Chow, W.-N. et al. Complement 3 deficiency impairs early pregnancy in mice. Mol. Reprod. Dev. 76, 647–655 (2009). Pham, C. T. & Ley, T. J. Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc. Natl. Acad. Sci. U. S. A. 96, 8627–32 (1999). Adkison, A. M., Raptis, S. Z., Kelley, D. G. & Pham, C. T. N. Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. J. Clin. Invest. 109, 363–371 (2002). Méthot, N. et al. Inhibition of the Activation of Multiple Serine Proteases with a Cathepsin C Inhibitor Requires Sustained Exposure to Prevent Pro-enzyme Processing. J. Biol. Chem. 282, 20836–20846 (2007). Meade, J. L. et al. Proteolytic Activation of the Cytotoxic Phenotype during Human NK Cell Development. J. Immunol. 183, 803–813 (2009). Menkhorst, E. M. et al. Decidual-Secreted Factors Alter Invasive Trophoblast Membrane and Secreted Proteins Implying a Role for Decidual Cell Regulation of Placentation. PLoS One 7, e31418 (2012). Zhu, X.-Y. et al. Blockade of CD86 Signaling Facilitates a Th2 Bias at the Maternal-Fetal Interface and Expands Peripheral CD4+CD25+ Regulatory T Cells to Rescue Abortion-Prone Fetuses1. Biol. Reprod. 72, 338–345 (2005). Wang, J. et al. Vascular endothelial growth factor affects dendritic cell activity in hypertensive disorders of pregnancy. Mol. Med. Rep. 12, 3781–3786 (2015). Whitley, G. S. J. & Cartwright, J. E. Trophoblast-mediated spiral artery remodelling: a role for apoptosis. J. Anat. 215, 21–26 (2009). Khong, T. Y., De Wolf, F., Robertson, W. B. & Brosens, I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br. J. Obstet. Gynaecol. 93, 1049–59 (1986). Urata, H., Kinoshita, A., Misono, K. S., Bumpus, F. M. & Husain, A. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J. Biol. Chem. 265, 22348–57 (1990). Tchougounova, E. et al. A Key Role for Mast Cell Chymase in the Activation of Pro-matrix Metalloprotease-9 and Pro-matrix Metalloprotease-2. J. Biol. Chem. 280, 9291–9296 (2005). Marx, L. et al. Decidual mast cells might be involved in the onset of human first-trimester abortion. Am. J. Reprod. Immunol. 41, 34–40 (1999). Garfield, R. E., Irani, A.-M., Schwartz, L. B., Bytautiene, E. & Romero, R. Structural and functional comparison of mast cells in the pregnant versus nonpregnant human uterus. Am. J. Obstet. Gynecol. 194, 261–267 (2006). Meyer, N. et al. Chymase-producing cells of the innate immune system are required for decidual vascular remodeling and fetal growth. Sci. Rep. 7, 45106 (2017). Clarson, L. H., Roberts, V. H. J., Hamark, B., Elliott, A. C. & Powell, T. Store-operated Ca 2+ entry in first trimester and term human placenta. J. Physiol. 550, 515–528 (2003). Jacobs, B. E., Liu, Y., Pulina, M. V., Golovina, V. A. & Hamlyn, J. M. Normal pregnancy: mechanisms underlying the paradox of a ouabain-resistant state with elevated endogenous ouabain, suppressed arterial sodium calcium exchange, and low blood pressure. Am. J. Physiol. Circ. Physiol. 302, H1317–H1329 (2012). Dykes, I. M. & Emanueli, C. Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA. Genomics. Proteomics Bioinformatics 15, 177–186 (2017). Herriges, M. J. et al. Long noncoding RNAs are spatially correlated with transcription factors and regulate lung development. Genes Dev. 28, 1363–1379 (2014).
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spelling	Laissue, Paul79782770600Quintero Ronderos, Paula JulianaDoctor en Ciencias BiomédicasFull timefc60ba2f-4743-401d-ab82-03e8a65ecd306002019-01-28T13:20:53Z2019-01-28T13:20:53Z2018-12-032018El aborto espontáneo recurrente (AER) se define como dos o más pérdidas consecutivas de la gestación antes de la semana 20 del desarrollo intrauterino. Esta patología afecta a aproximadamente entre el 1% y el 5% de las parejas. La etiología del AER se puede dividir en causas no-genéticas como genéticas. Sin embargo, ~50% de los casos se considera idiopático. De manera análoga, la etiología molecular de la falla de implantación recurrente (FIR), definida como la falla de la implantación en al menos 2 o más ciclos consecutivos de fertilización in vitro, es poco conocida. La etiología molecular del AER y de la FIR está asociada potencialmente a variantes de secuencia en cientos de genes candidato que participan en las cascadas moleculares fisiológicas de la implantación y durante toda la gestación. La aproximación gen candidato, usando la secuenciación de Sanger, ha sido de utilidad para la descripción de pocos genes implicados en el AER. La secuenciación de siguiente generación (NGS) ha sido una herramienta eficiente puesto que permite el estudio simultáneo de múltiples genes relacionados con enfermedades complejas. En la primera parte de este trabajo de tesis se utilizó la aproximación NGS-exoma para identificar nuevos genes y mutaciones potencialmente implicadas en el desarrollo del AER. Algunas de las mutaciones encontradas por este abordaje fueron estudiadas mediante ensayos funcionales in vitro para determinar su posible efecto deletéreo. La identificación de la variante THBD p.Trp153Gly en mujeres colombianas con AER y su validación mediante ensayos funcionales in vitro sugiere, por primera vez, una relación directa entre formas mutantes de esta proteína y la fisiopatología del AER, considerándose como un posible marcador molecular para el diagnóstico en pacientes colombianas con AER idiopático. En la segunda parte del presente trabajo de tesis identificamos y estudiamos funcionalmente nuevas mutaciones de FOXD1, un gen relevante en la fisiología endometrial y placentaria, identificadas en pacientes FIR, AER, preeclampsia (PE) y retardo del crecimiento intrauterino (RCIU). Los ensayos funcionales in vitro demostraron que las mutaciones FOXD1-p.His267Tyr y FOXD1-p.Arg57del. modifican la transactivación del promotor de C3, contribuyendo con el fenotipo. FOXD1 podría considerarse en consecuencia un marcador molecular diagnóstico para las pacientes con AER, FIR, RCIU y PE. Por último, ensayos por inmunoprecipitación de la cromatina secuenciación NGS (ChIP-seq) permitieron determinar potenciales nuevos genes blanco directos de FOXD1 (CTSC, CD86, CMA1 y TRPC6) en un contexto placentario. La información generada durante este trabajo de tesis aporta al conocimiento sobre el origen genético del AER, la FIR, y el RCIU/PE. Estos resultados podrían ser de utilidad para los especialistas clínicos en el contexto del desarrollo de la medicina traslacional.Recurrent pregnancy loss (RPL) is defined as the loss of two or more consecutive and spontaneous miscarriages before the 20th week of gestation. This pathology affects ~1% to 5% of the couples. The RPL aetiology is classified as non-genetics and genetics. However, the 50% of the cases remains idiopathic. Similarly, the aetiology of the recurrent implantation failure (RIF), defined as the implantation failure in at least 2 or more consecutive cycles of in vitro fertilization (IVF), is poorly understood. To note, the molecular RPL and RIF aetiology is potentially associated with hundreds of genes which participate in the physiological molecular pathways related to the implantation and gestation. The candidate gene approach using Sanger sequencing has been useful to identify some genes associated with RPL. However, the next generation sequencing (NGS) has been an effective tool to overcome this limitation because it allows the simultaneous study of multiple genes related to complex diseases. In first part of this thesis, we used the NGS-exome approach to identify new genes and mutation potentially implicated in the development of RPL. Some of the mutations found by this approach were tested by functional in vitro assays to determine their possible deleterious effect within the pathology. The identification of the variant THBD p.Trp153Gly in Colombian women with RPL and its validation through functional in vitro assays suggested, for the first time, a direct association with the RPL pathophysiology. Therefore, it may be considered as a molecular biomarker for the RPL diagnosis in Colombian patients. In the second part of this thesis, we identified and studied the potential implication of new FOXD1 mutations, a relevant gene in the endometrium and placenta physiology, in patients with RIF, RPL, preeclampsia (PE) and intrauterine growth restriction (IUGR). The functional in vitro assays demonstrated that FOXD1 p.His267Tyr and FOXD1 p.Arg57del mutations modify the C3 promoter transactivation, thus contributing to the phenotype. Therefore, FOXD1 could be considered a molecular biomarker for the diagnosis of RPL, RIF, PE and IUGR patients. The chromatin immunoprecipitation assays (ChIP) allowed to determine new direct FOXD1 target genes (CTSC, CD86, CMA1 y TRPC6) within the placenta context. The information generated during this thesis contributes to the general knowledge about the origin and development of RPL, RIF, PE/IUGR. These results might be useful for the clinical specialist in a context of translational medicine.2021-01-29 01:01:01: Script de automatizacion de embargos. info:eu-repo/date/embargoEnd/2021-01-28application/pdfhttps://doi.org/10.48713/10336_18933 http://repository.urosario.edu.co/handle/10336/18933spaUniversidad del RosarioFacultad de Ciencias Naturales y MatemáticasDoctorado en Ciencias BiomédicasAtribución-NoComercial-SinDerivadas 2.5 ColombiaAbierto (Texto Completo)EL AUTOR, manifiesta que la obra objeto de la presente autorización es original y la realizó sin violar o usurpar derechos de autor de terceros, por lo tanto la obra es de exclusiva autoría y tiene la titularidad sobre la misma. 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Para el correcto ejercicio de mi derecho de habeas data cuento con la cuenta de correo habeasdata@urosario.edu.co, donde previa identificación podré solicitar la consulta, corrección y supresión de mis datos.http://creativecommons.org/licenses/by-nc-nd/2.5/co/http://purl.org/coar/access_right/c_abf2Li, T. C. et al. Recurrent miscarriage: aetiology, management and prognosis. Hum. Reprod. Update 8, 463–81 (2002).Rai, R. & Regan, L. Recurrent miscarriage. Lancet 368, 601–611 (2006).Stirrat, G. M. Recurrent miscarriage. Lancet 336, 673–675 (1990).Hogge, W. A., Byrnes, A. L., Lanasa, M. C. & Surti, U. The clinical use of karyotyping spontaneous abortions. Am. J. Obstet. Gynecol. 189, 397-400; discussion 400–2 (2003).Bricker Leanne & Farquharson Roy G. Recurring miscarriage. Obstet. Gynaecol. 2, 17–23 (2000).Rai, R. S., Clifford, K., Cohen, H. & Regan, L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum. Reprod. 10, 3301–3304 (1995).Santos, T. da S. et al. Antiphospholipid syndrome and recurrent miscarriage: A systematic review and meta-analysis. J. Reprod. Immunol. 123, 78–87 (2017).Mak, I. Y. H. et al. Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro. J. Clin. Endocrinol. Metab. 87, 2581–2588 (2002).Bose, P. et al. Heparin and aspirin attenuate placental apoptosis in vitro: Implications for early pregnancy failure. Am. J. Obstet. Gynecol. 192, 23–30 (2005).Salim, R., Regan, L., Woelfer, B., Backos, M. & Jurkovic, D. A comparative study of the morphology of congenital uterine anomalies in women with and without a history of recurrent first trimester miscarriage. Hum. Reprod. (2003). doi:10.1093/humrep/deg030Grimbizis, G. F., Camus, M., Tarlatzis, B. C., Bontis, J. N. & Devroey, P. Clinical implications of uterine malformations and hysteroscopic treatment results. Human Reproduction Update 7, 161–174 (2001).Hart, R. et al. A prospective controlled study of the effect of intramural uterine fibroids on the outcome of assisted conception. Human reproduction (Oxford, England) 16, (2001).Rackow, B. W. & Taylor, H. S. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil. Steril. 93, 2027–2034 (2010).Hirahara, F. et al. Hyperprolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trials. Fertil. Steril. 70, 246–252 (1998).Garzia, E. et al. Lack of expression of endometrial prolactin in early implantation failure: A pilot study. Hum. Reprod. 19, 1911–1916 (2004).Craig, L. B., Ke, R. W. & Kutteh, W. H. Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss. Fertil. Steril. 78, 487–490 (2002).Rai, R., Backos, M., Rushworth, F. & Regan, L. Polycystic ovaries and recurrent miscarriage--a reappraisal. Hum. Reprod. 15, 612–615 (2000).Kaur, R. & Gupta, K. Endocrine dysfunction and recurrent spontaneous abortion: An overview. Int. J. Appl. Basic Med. Res. 6, 79 (2016).Clifford, K., Flanagan, A. M. & Regan, L. Endometrial CD56+ natural killer cells in women with recurrent miscarriage: a histomorphometric study. Hum. Reprod. 14, 2727–2730 (1999).Reinhard, G., Noll, A., Schlebusch, H., Mallmann, P. & Ruecker, A. Shifts in the TH1/TH2 balance during human pregnancy correlate with apoptotic changes. Biochem. Biophys. Res. Commun. 245, 933–938 (1998).Beaman, K. D. et al. Immune Etiology of Recurrent Pregnancy Loss and Its Diagnosis. Am. J. Reprod. Immunol. 67, 319–325 (2012).Ralph, S. G., Rutherford, A. J. & Wilson, J. D. Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study. BMJ 319, 220–223 (1999).Hay, P. E. et al. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 308, 295–298 (1994).Isik, G., Demirezen, Ş., Dönmez, H. & Beksaç, M. Bacterial vaginosis in association with spontaneous abortion and recurrent pregnancy losses. J. Cytol. 33, 135 (2016).Giakoumelou, S. et al. The role of infection in miscarriage. Hum. Reprod. Update 22, 116–133 (2016).Jia, C.-W. et al. Aneuploidy in Early Miscarriage and its Related Factors. Chin. Med. J. (Engl). 128, 2772 (2015).Hyde, K. J. & Schust, D. J. Genetic Considerations in Recurrent Pregnancy Loss. Cold Spring Harb. Perspect. Med. 5, a023119–a023119 (2015).Sierra S & Stephenson M. Genetics of recurrent pregnancy loss. Semin Reprod Med. 24, 17–24. (2006).Stephenson, M. D., Awartani, K. A. & Robinson, W. P. Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study. Hum. Reprod. (2002). doi:10.1016/S0015-0282(01)02285-3Hassold, T. & Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nat. Rev. Genet. 2, 280–291 (2001).Rubio, C. et al. Chromosomal abnormalities and embryo development in recurrent miscarriage couples. Hum. Reprod. (2003). doi:10.1093/humrep/deg015Choi, T. Y., Lee, H. M., Park, W. K., Jeong, S. Y. & Moon, H. S. Spontaneous abortion and recurrent miscarriage: A comparison of cytogenetic diagnosis in 250 cases. Obstet. Gynecol. Sci. 57, 518 (2014).Coelho, F. F. et al. Detection of aneuploidies in spontaneous abortions by quantitative fluorescent PCR with short tandem repeat markers: a retrospective study. Genet. Mol. Res. 15, (2016).ESHRE Capri Workshop Group. Genetic aspects of female reproduction. Hum. Reprod. Update 14, 293–307. (2008).Menasha, J., Levy, B., Hirschhorn, K. & Kardon, N. B. Incidence and spectrum of chromosome abnormalities in spontaneous abortions: New insights from a 12-year study. Genet. Med. 7, 251–263 (2005).Uehara, S. et al. Preferential X-chromosome inactivation in women with idiopathic recurrent pregnancy loss. in Fertility and Sterility 76, 908–914 (2001).Sangha, K. K., Stephenson, M. D., Brown, C. J. & Robinson, W. P. Extremely skewed X-chromosome inactivation is increased in women with recurrent spontaneous abortion. American journal of human genetics 65, 913–917 (1999).Aldrich, C. L. et al. HLA-G genotypes and pregnancy outcome in couples with unexplained recurrent miscarriage. Molecular human reproduction 7, (2001).Pfeiffer, K. A., Fimmers, R., Engels, G., van der Ven, H. & van der Ven, K. The HLA-G genotype is potentially associated with idiopathic recurrent spontaneous abortion. Mol. Hum. Reprod. 7, 373–8 (2001).Kovalevsky, G., Gracia, C. R., Berlin, J. A., Sammel, M. D. & Barnhart, K. T. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch. Intern. Med. 164, 558–563 (2004).Rey, E., Kahn, S. R., David, M. & Shrier, I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet (London, England) 361, 901–8 (2003).Rai, R., Backos, M., Elgaddal, S., Shlebak, A. & Regan, L. Factor V Leiden and recurrent miscarriage-prospective outcome of untreated pregnancies. Hum. Reprod. 17, 442–445 (2002).Laissue, P. et al. Association of FOXD1 variants with adverse pregnancy outcomes in mice and humans. Open Biol. 6, 160109 (2016).Polanski, L. T. et al. What exactly do we mean by ‘recurrent implantation failure’? A systematic review and opinion. Reprod. Biomed. Online 28, 409–423 (2014).Croucher, C. A., Lass, A., Margara, R. & Winston, R. M. Predictive value of the results of a first in-vitro fertilization cycle on the outcome of subsequent cycles. Hum. Reprod. 13, 403–8 (1998).Yang, R. et al. Biochemical pregnancy and spontaneous abortion in first IVF cycles are negative predictors for subsequent cycles: an over 10,000 cases cohort study. Arch. Gynecol. Obstet. 292, 453–458 (2015).Simon, A. & Laufer, N. Assessment and treatment of repeated implantation failure (RIF). J. Assist. Reprod. Genet. 29, 1227–1239 (2012).Rinehart, J. Recurrent implantation failure: Definition. J. Assist. Reprod. Genet. 24, 284–287 (2007).Timeva, T., Shterev, A. & Kyurkchiev, S. Recurrent implantation failure: The role of the endometrium. J. Reprod. Infertil. 15, 173–183 (2014).Simon, A. & Laufer, N. Repeated implantation failure: Clinical approach. Fertil. Steril. 97, 1039–1043 (2012).El-Toukhy, T. & Taranissi, M. Towards better quality research in recurrent implantation failure: standardizing its definition is the first step. Reprod. Biomed. Online 12, 383–5 (2006).Levi Setti, P. E. et al. Implantation failure in assisted reproduction technology and a critical approach to treatment. Ann. N. Y. Acad. Sci. 1034, 184–199 (2004).Ocal, P. et al. Recurrent implantation failure is more frequently seen in female patients with poor prognosis. Int. J. Fertil. Steril. 6, 71–8 (2012).Regan, L., Braude, P. R. & Trembath, P. L. Influence of past reproductive performance on risk of spontaneous abortion. BMJ 299, 541–545 (1989).Knudsen, U. B., Hansen, V., Juul, S. & Secher, N. J. Prognosis of a new pregnancy following previous spontaneous abortions. Eur. J. Obstet. Gynecol. Reprod. Biol. 39, 31–36 (1991).Strobino, B. et al. Characteristics of women with recurrent spontaneous abortions and women with favorable reproductive histories. Am. J. Public Health 76, 986–91 (1986).Kolte, A. M. M. et al. A genome-wide scan in affected sibling pairs with idiopathic recurrent miscarriage suggests genetic linkage. MHR Basic Sci. Reprod. Med. 17, 379–385 (2011).Shekouhi, S. et al. Identification of Xq22.1-23 as a region linked with hereditary recurrent spontaneous abortion in a family. Iran. J. Reprod. Med. 11, 659–64 (2013).Li Wang, Zeng Chan Wang, Cui Xie, Xiao Feng Liu & Mao Sheng Yang. Genome-Wide Screening for Risk Loci of Idiopathic Recurrent Miscarriage in a Han Chinese Population: A Pilot Study. Reprod. Sci. 17, 578–584 (2010).Kaare, M. et al. Variations in the thrombomodulin and endothelial protein C receptor genes in couples with recurrent miscarriage. Hum. Reprod. 22, 864–8 (2007).Mercier, E., Lissalde-Lavigne, G. & Gris, J.-C. JAK2 V617F Mutation in Unexplained Loss of First Pregnancy. N. Engl. J. Med. 357, 1984–1985 (2007).Kaare, M., Painter, J. N., Ulander, V. M., Kaaja, R. & Aittomäki, K. Variations of the amnionless gene in recurrent spontaneous abortions. Mol. Hum. Reprod. 12, 25–29 (2006).Neveling, K. et al. A Post-Hoc Comparison of the Utility of Sanger Sequencing and Exome Sequencing for the Diagnosis of Heterogeneous Diseases. Hum. Mutat. 34, 1721–1726 (2013).Baudhuin, L. M. et al. Confirming Variants in Next-Generation Sequencing Panel Testing by Sanger Sequencing. J. Mol. Diagnostics 17, 456–461 (2015).Laissue, P. Aetiological coding sequence variants in non-syndromic premature ovarian failure: From genetic linkage analysis to next generation sequencing. Mol. Cell. Endocrinol. 411, 243–257 (2015).Lee, K. Y. & DeMayo, F. J. Animal models of implantation. Reproduction 128, 679–695 (2004).Wilcox, A. J., Baird, D. D. & Weinberg, C. R. Time of Implantation of the Conceptus and Loss of Pregnancy. N. Engl. J. Med. 340, 1796–1799 (1999).Wimsatt, W. A. Some comparative aspects of implantation. Biol. Reprod. 12, 1–40 (1975).Aghajanova, L. et al. Comparative Transcriptome Analysis of Human Trophectoderm and Embryonic Stem Cell-Derived Trophoblasts Reveal Key Participants in Early Implantation. Biol. Reprod. 86, 1–21 (2012).Cha, J., Sun, X. & Dey, S. K. Mechanisms of implantation: strategies for successful pregnancy. Nat. Med. 18, 1754–1767 (2012).King, A. Uterine leukocytes and decidualization. Hum. Reprod. Update 6, 28–36 (2000).Christian, M. et al. Interferon-gamma modulates prolactin and tissue factor expression in differentiating human endometrial stromal cells. Endocrinology 142, 3142–51 (2001).Irwin, J. C. & Giudice, L. C. Insulin-like growth factor binding protein-1 binds to placental cytotrophoblast alpha5beta1 integrin and inhibits cytotrophoblast invasion into decidualized endometrial stromal cultures. Growth Horm. IGF Res. 8, 21–31 (1998).Kusama, K., Yoshie, M., Tamura, K., Imakawa, K. & Tachikawa, E. EPAC2-mediated calreticulin regulates LIF and COX2 expression in human endometrial glandular cells. J. Mol. Endocrinol. 54, 17–24 (2014).Li, Q. et al. WNT4 Acts Downstream of BMP2 and Functions via β-Catenin Signaling Pathway to Regulate Human Endometrial Stromal Cell Differentiation. Endocrinology 154, 446–457 (2013).Aghajanova, L. Leukemia inhibitory factor and human embryo implantation. Ann N Y Acad Sci 1034, 176–183 (2004).Kojima, K. et al. Expression of leukaemia inhibitory factor (LIF) receptor in human placenta: a possible role for LIF in the growth and differentiation of trophoblasts. Hum. Reprod. 10, 1907–11 (1995).Carson, D. D. et al. Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening. Mol. Hum. Reprod. 8, 871–879 (2002).Kao, L. C. et al. Global gene profiling in human endometrium during the window of implantation. Endocrinology 143, 2119–2138 (2002).Popovici, R. M., Kao, L. C. & Giudice, L. C. Discovery of new inducible genes in in vitro decidualized human endometrial stromal cells using microarray technology. Endocrinology 141, 3510–3513 (2000).Uegaki, K. et al. PTEN is involved in the signal transduction pathway of contact inhibition in endometrial cells. Cell Tissue Res. 323, 523–528 (2006).Ejskjaer, K. et al. Expression of the epidermal growth factor system in human endometrium during the menstrual cycle. Mol. Hum. Reprod. 11, 543–551 (2005).Kats, R., Al-Akoum, M., Guay, S., Metz, C. & Akoum, A. Cycle-dependent expression of macrophage migration inhibitory factor in the human endometrium. Hum. Reprod. 20, 3518–3525 (2005).Print, C. et al. Soluble factors from human endometrium promote angiogenesis and regulate the endothelial cell transcriptome. Hum. Reprod. 19, 2356–2366 (2004).Stavreus-Evers, A. et al. Co-existence of heparin-binding epidermal growth factor-like growth factor and pinopodes in human endometrium at the time of implantation. Mol. Hum. Reprod. 8, 765–769 (2002).Nikas, G. & Aghajanova, L. Endometrial pinopodes: some more understanding on human implantation? Reprod. Biomed. Online 4 Suppl 3, 18–23 (2002).Jones, R. L., Stoikos, C., Findlay, J. K. & Salamonsen, L. A. TGF-?? superfamily expression and actions in the endometrium and placenta. Reproduction (2006). doi:10.1530/rep.1.01076Li, Y.-H., Kuo, C.-H., Shi, G.-Y. & Wu, H.-L. The role of thrombomodulin lectin-like domain in inflammation. J. Biomed. Sci. 19, 34 (2012).Conway, E. M. et al. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. J. Exp. Med. 196, 565–77 (2002).Van Dreden, P., Woodhams, B., Rousseau, A., Favier, M. & Favier, R. Comparative evaluation of Tissue factor and Thrombomodulin activity changes during normal and idiopathic early and late foetal loss: The cause of hypercoagulability? Thromb. Res. 129, 787–792 (2012).Isermann, B. et al. The thrombomodulin–protein C system is essential for the maintenance of pregnancy. Nat. Med. 9, 331–337 (2003).Griesshammer, M., Struve, S. & Harrison, C. M. Essential thrombocythemia/polycythemia vera and pregnancy: The need for an observational study in Europe. Semin. Thromb. Hemost. 32, 422–429 (2006).Kralovics, R. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–90 (2005).Melillo, L. et al. Outcome of 122 pregnancies in essential thrombocythemia patients: A report from the Italian registry. Am. J. Hematol. 84, 636–640 (2009).Passamonti, F. et al. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617V>F) mutation. Blood 110, 485–9 (2007).Barber, L. J. et al. Comprehensive genomic analysis of a BRCA2 deficient human pancreatic cancer. PLoS One (2011). doi:10.1371/journal.pone.0021639Laissue, P. The molecular complexity of primary ovarian insufficiency aetiology and the use of massively parallel sequencing. Mol. Cell. Endocrinol. 460, 170–180 (2018).Çalişkan, M. et al. Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13. Hum. Mol. Genet. (2011). doi:10.1093/hmg/ddq569Veltman, J. A. & Brunner, H. G. De novo mutations in human genetic disease. Nature Reviews Genetics (2012). doi:10.1038/nrg3241Hrdlickova, B., de Almeida, R. C., Borek, Z. & Withoff, S. Genetic variation in the non-coding genome: Involvement of micro-RNAs and long non-coding RNAs in disease. Biochim. Biophys. Acta - Mol. Basis Dis. 1842, 1910–1922 (2014).Huang, Q. Genetic Study of Complex Diseases in the Post-GWAS Era. J. Genet. Genomics 42, 87–98 (2015).Gibson, G. Rare and common variants: twenty arguments. Nat. Rev. Genet. 13, 135–145 (2012).Lettre, G. Rare and low-frequency variants in human common diseases and other complex traits. J. Med. Genet. 51, 705–14 (2014).Zuk, O. et al. Searching for missing heritability: Designing rare variant association studies. Proc. Natl. Acad. Sci. 111, E455–E464 (2014).Mitropoulos, K. et al. Success stories in genomic medicine from resource-limited countries. Hum. Genomics 9, 11 (2015).Fonseca, D. J. et al. Next generation sequencing in women affected by nonsyndromic premature ovarian failure displays new potential causative genes and mutations. Fertil. Steril. 104, 154–62.e2 (2015).Patiño, L. C. et al. Exome Sequencing Is an Efficient Tool for Variant Late-Infantile Neuronal Ceroid Lipofuscinosis Molecular Diagnosis. PLoS One 9, e109576 (2014).Ortega-Recalde, O. et al. Whole-Exome Sequencing Enables Rapid Determination of Xeroderma Pigmentosum Molecular Etiology. PLoS One 8, e64692 (2013).Diggle, C. P. et al. Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis. Hum. Mutat. 33, 1175–1181 (2012).Patiño, L. C. et al. New mutations in non-syndromic primary ovarian insufficiency patients identified via whole-exome sequencing. Hum. Reprod. 32, 1512–1520 (2017).Carlosama, C. et al. A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency. Hum. Mol. Genet. 26, 3161–3166 (2017).Qiao, Y. et al. Whole exome sequencing in recurrent early pregnancy loss. Mol. Hum. Reprod. 22, 364–72 (2016).Sõber, S. et al. RNA sequencing of chorionic villi from recurrent pregnancy loss patients reveals impaired function of basic nuclear and cellular machinery. Sci. Rep. 6, 38439 (2016).Wang, J. mei et al. Deep-sequencing identification of differentially expressed miRNAs in decidua and villus of recurrent miscarriage patients. Arch. Gynecol. Obstet. 293, 1125–1135 (2016).Quintero-Ronderos, P. et al. Novel genes and mutations in patients affected by recurrent pregnancy loss. PLoS One 12, e0186149 (2017).Lissalde-Lavigne, G. et al. Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case-control ‘NOHA first’ study. J. Thromb. Haemost. 3, 2178–84 (2005).Wang, Q., Shashikant, C. S., Jensen, M., Altman, N. S. & Girirajan, S. Novel metrics to measure coverage in whole exome sequencing datasets reveal local and global non-uniformity. Sci. Rep. 7, 885 (2017).Lee, S. M., Wu, B. & Kersey, J. H. Likelihood-Based Approach to Gene Set Enrichment Analysis with a Finite Mixture Model. Stat. Biosci. 6, 38–54 (2014).Heifetz, A. et al. The Fragment Molecular Orbital Method Reveals New Insight into the Chemical Nature of GPCR–Ligand Interactions. J. Chem. Inf. Model. 56, 159–172 (2016).Fedorov, D. G., Nagata, T. & Kitaura, K. Exploring chemistry with the fragment molecular orbital method. Phys. Chem. Chem. Phys. 14, 7562 (2012).Stewart, J. J. MOPAC: a semiempirical molecular orbital program. J. Comput. Aided. Mol. Des. 4, 1–105 (1990).Hitaoka, S., Chuman, H. & Yoshizawa, K. A QSAR study on the inhibition mechanism of matrix metalloproteinase-12 by arylsulfone analogs based on molecular orbital calculations. Org. Biomol. Chem. 13, 793–806 (2015).Rozen, S. & Skaletsky, H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol. Biol. 132, 365–86 (2000).Hu, Z. et al. Structural Insights into the pH-Dependent Conformational Change and Collagen Recognition of the Human Mannose Receptor. Structure 26, 60–71.e3 (2018)Roy, A., Kucukural, A. & Zhang, Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nat. Protoc. 5, 725–738 (2010).Zhang, Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics 9, 40 (2008).Yang, J. et al. The I-TASSER Suite: protein structure and function prediction. Nat. Methods 12, 7–8 (2015).Pettersen, E. F. et al. UCSF Chimera?A visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).Dunbrack, R. L. Rotamer libraries in the 21st century. Curr. Opin. Struct. Biol. 12, 431–40 (2002).Phillips, J. C. et al. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781–1802 (2005).Huang, J. & MacKerell, A. D. CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data. J. Comput. Chem. 34, 2135–2145 (2013).Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. & Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926–935 (1983).Benkert, P., Biasini, M. & Schwede, T. Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics 27, 343–350 (2011).Chen, V. B. et al. MolProbity : all-atom structure validation for macromolecular crystallography. Acta Crystallogr. Sect. D Biol. Crystallogr. 66, 12–21 (2010).Humphrey, W., Dalke, A. & Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph. 14, 33–38 (1996).Voss, N. R. & Gerstein, M. 3V: cavity, channel and cleft volume calculator and extractor. Nucleic Acids Res. 38, W555–W562 (2010).Søndergaard, C. R., Olsson, M. H. M., Rostkowski, M. & Jensen, J. H. Improved Treatment of Ligands and Coupling Effects in Empirical Calculation and Rationalization of p K a Values. J. Chem. Theory Comput. 7, 2284–2295 (2011).Baker, N. A., Sept, D., Joseph, S., Holst, M. J. & McCammon, J. A. Electrostatics of nanosystems: Application to microtubules and the ribosome. Proc. Natl. Acad. Sci. 98, 10037–10041 (2001).Dolinsky, T. J., Nielsen, J. E., McCammon, J. A. & Baker, N. A. PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations. Nucleic Acids Res. 32, W665–W667 (2004).Sims, D., Sudbery, I., Ilott, N. E., Heger, A. & Ponting, C. P. Sequencing depth and coverage: key considerations in genomic analyses. Nat. Rev. Genet. 15, 121–132 (2014).Meynert, A. M., Ansari, M., FitzPatrick, D. R. & Taylor, M. S. Variant detection sensitivity and biases in whole genome and exome sequencing. BMC Bioinformatics 15, 247 (2014).Kim, K. et al. Effect of Next-Generation Exome Sequencing Depth for Discovery of Diagnostic Variants. Genomics Inform. 13, 31 (2015).Kiezun, A. et al. Exome sequencing and the genetic basis of complex traits. Nat. Genet. 44, 623–630 (2012)Goldstein, D. B. et al. Sequencing studies in human genetics: Design and interpretation. Nat. Rev. Genet. 14, 460–470 (2013).Tennessen, J. A. et al. Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes. Sci. (New York, NY) 337, 64–69 (2012).O’Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012).Delcour, C. et al. ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure. Genet. Med. (2018). doi:10.1038/s41436-018-0287-yThusberg, J., Olatubosun, A. & Vihinen, M. Performance of mutation pathogenicity prediction methods on missense variants. Hum. Mutat. 32, 358–368 (2011).Walters-Sen, L. C. et al. Variability in pathogenicity prediction programs: impact on clinical diagnostics. Mol. Genet. Genomic Med. 3, 99–110 (2015).Dawood, F., Mountford, R., Farquharson, R. & Quenby, S. Genetic polymorphisms on the factor V gene in women with recurrent miscarriage and acquired APCR. Hum. Reprod. 22, 2546–2553 (2007).Altintas, A. et al. Factor V Leiden and G20210A prothrombin mutations in patients with recurrent pregnancy loss: data from the southeast of Turkey. Ann. Hematol. 86, 727–731 (2007).Aytekin, E., Ergun, S. G., Ergun, M. A. & Percin, F. E. Evaluation of GenoFlow Thrombophilia Array Test Kit in Its Detection of Mutations in Factor V Leiden (G1691A), Prothrombin G20210A, MTHFR C677T and A1298C in Blood Samples from 113 Turkish Female Patients. Genet. Test. Mol. Biomarkers 18, 717–721 (2014).Asselta, R., Tenchini, M. L. & Duga, S. Inherited defects of coagulation factor V: the hemorrhagic side. J. Thromb. Haemost. 4, 26–34 (2006).Steen, M. & Dahlbäck, B. Thrombin-mediated proteolysis of factor V resulting in gradual B-domain release and exposure of the factor Xa-binding site. J. Biol. Chem. 277, 38424–30 (2002).Erdogan, E., Bukys, M. A. & Kalafatis, M. The contribution of amino acid residues 1508-1515 of factor V to light chain generation. J. Thromb. Haemost. 6, 118–24 (2008).Peng, W., Quinn-Allen, M. A. & Kane, W. H. Mutation of hydrophobic residues in the factor Va C1 and C2 domains blocks membrane-dependent prothrombin activation. J. Thromb. Haemost. 3, 351–4 (2005).Otto, P. & Ladik, J. Investigation of the interaction between molecules at medium distances. Chem. Phys. 8, 192–200 (1975).Fiedler, Benjamin & Friedrich, Joachim. (2017). The incremental method - Theory and applications in chemistry and physics. 13. 132-190. 10.1039/9781782626862-00132.Xie, W. & Gao, J. Design of a Next Generation Force Field: The X-POL Potential. J. Chem. Theory Comput. 3, 1890–1900 (2007).Batra, J. et al. Matrix Metalloproteinase-10 (MMP-10) Interaction with Tissue Inhibitors of Metalloproteinases TIMP-1 and TIMP-2: BINDING STUDIES AND CRYSTAL STRUCTURE. J. Biol. Chem. 287, 15935–15946 (2012).Maruyama, I., Bell, C. E. & Majerus, P. W. Thrombomodulin is found on endothelium of arteries, veins, capillaries, and lymphatics, and on syncytiotrophoblast of human placenta. J. Cell Biol. 101, 363–71 (1985).Martin, F. A., Murphy, R. P. & Cummins, P. M. Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects. Am. J. Physiol. Heart Circ. Physiol. 304, H1585-97 (2013).Masini, S. et al. Thrombin-activatable fibrinolysis inhibitor polymorphisms and recurrent pregnancy loss. Fertil. Steril. 92, 694–702 (2009).Ito, T., Kakihana, Y. & Maruyama, I. Thrombomodulin as an intravascular safeguard against inflammatory and thrombotic diseases. Expert Opin. Ther. Targets 20, 151–158 (2016).Delvaeye, M. et al. Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome. N. Engl. J. Med. 361, 345–357 (2009).Huang, H.-C. et al. Thrombomodulin-mediated cell adhesion: involvement of its lectin-like domain. J. Biol. Chem. 278, 46750–9 (2003).Stortoni, P. et al. Placental thrombomodulin expression in recurrent miscarriage. Reprod. Biol. Endocrinol. 8, 1 (2010).Suzuki, K. et al. A domain composed of epidermal growth factor-like structures of human thrombomodulin is essential for thrombin binding and for protein C activation. J. Biol. Chem. 264, 4872–4876 (1989).Sood, R. et al. Maternal Par4 and platelets contribute to defective placenta formation in mouse embryos lacking thrombomodulin. Blood 112, 585–91 (2008).de Saint Martin, L. et al. Increased thrombin generation measured in the presence of thrombomodulin in women with early pregnancy loss. Fertil. Steril. 95, 1813–5.e1 (2011).Li, Y.-H., Shi, G.-Y. & Wu, H.-L. The role of thrombomodulin in atherosclerosis: from bench to bedside. Cardiovasc. Hematol. Agents Med. Chem. 4, 183–7 (2006).Parodi, A., Cummings, R. D. & Aebi, M. in Essentials of Glycobiology 3rd Editio, (2017).Suzuki, K. et al. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. EMBO J. 6, 1891–7 (1987).Ito, T. et al. Proteolytic Cleavage of High Mobility Group Box 1 Protein by Thrombin-Thrombomodulin Complexes. Arterioscler. Thromb. Vasc. Biol. 28, 1825–1830 (2008).Abeyama, K. et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J. Clin. Invest. 115, 1267–1274 (2005).Rossini, A. et al. HMGB1-stimulated human primary cardiac fibroblasts exert a paracrine action on human and murine cardiac stem cells. J. Mol. Cell. Cardiol. 44, 683–693 (2008).Yoshihara-Hirata, C. et al. Anti-HMGB1 Neutralizing Antibody Attenuates Periodontal Inflammation and Bone Resorption in a Murine Periodontitis Model. Infect. Immun. 86, (2018).Alsousi, A. A. & Igwe, O. J. Redox-active trace metal-induced release of high mobility group box 1(HMGB1) and inflammatory cytokines in fibroblast-like synovial cells is Toll-like receptor 4 (TLR4) dependent. Biochim. Biophys. Acta - Mol. Basis Dis. 1864, 3847–3858 (2018)Shirasuna, K. et al. AGEs and HMGB1 Increase Inflammatory Cytokine Production from Human Placental Cells, Resulting in an Enhancement of Monocyte Migration. Am. J. Reprod. Immunol. 75, 557–568 (2016).Amin, A. R. & Islam, A. B. M. M. K. Genomic Analysis and Differential Expression of HMG and S100A Family in Human Arthritis: Upregulated Expression of Chemokines, IL-8 and Nitric Oxide by HMGB1. DNA Cell Biol. 33, 550–565 (2014)Huang, Q. T. et al. Advanced glycation end products as an upstream molecule triggers ROS-induced sFlt-1 production in extravillous trophoblasts: A novel bridge between oxidative stress and preeclampsia. Placenta 34, 1177–1182 (2013).Min, H. J. et al. ROS-dependent HMGB1 secretion upregulates IL-8 in upper airway epithelial cells under hypoxic condition. Mucosal Immunol. 10, 685–694 (2017).Sagheddu, R. et al. Targeting RAGE as a potential therapeutic approach to Duchenne muscular dystrophy. Hum. Mol. Genet. 27, 3734–3746 (2018).Patel, V. et al. The stretch responsive microRNA miR-148a-3p is a novel repressor of IKBKB, NF- κ B signaling, and inflammatory gene expression in human aortic valve cells. FASEB J. 29, 1859–1868 (2015).Anjana, R. et al. Aromatic-aromatic interactions in structures of proteins and protein-DNA complexes: a study based on orientation and distance. Bioinformation 8, 1220–1224 (2012).Bignucolo, O., Leung, H. T. A., Grzesiek, S. & Bernèche, S. Backbone Hydration Determines the Folding Signature of Amino Acid Residues. J. Am. Chem. Soc. 137, 4300–4303 (2015)Zhang, Z., Witham, S. & Alexov, E. On the role of electrostatics in protein–protein interactions. Phys. Biol. 8, 035001 (2011).Andersson, U. et al. High Mobility Group 1 Protein (Hmg-1) Stimulates Proinflammatory Cytokine Synthesis in Human Monocytes. J. Exp. Med. 192, 565–570 (2000).Bhutada, S. et al. High mobility group box 1 (HMGB1) protein in human uterine fluid and its relevance in implantation. Hum. Reprod. 29, 763–780 (2014).Riesewijk, A. et al. Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology. Mol. Hum. Reprod. 9, 253–64 (2003).Kwak-Kim, J. Y. H., Gilman-Sachs, A. & Kim, C. E. in Immunology of Gametes and Embryo Implantation 64–79 (KARGER, 2005). doi:10.1159/000087821Bates, M. D., Quenby, S., Takakuwa, K., Johnson, P. M. & Vince, G. S. Aberrant cytokine production by peripheral blood mononuclear cells in recurrent pregnancy loss? Hum. Reprod. 17, 2439–44 (2002).Tian, H., McKnight, S. L. & Russell, D. W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11, 72–82 (1997).Takeda, N. et al. Endothelial PAS domain protein 1 gene promotes angiogenesis through the transactivation of both vascular endothelial growth factor and its receptor, Flt-1. Circ. Res. 95, 146–53 (2004).Maemura, K. et al. Generation of a dominant-negative mutant of endothelial PAS domain protein 1 by deletion of a potent C-terminal transactivation domain. J. Biol. Chem. 274, 31565–70 (1999).Depoix, C. L. L., de Selliers, I., Hubinont, C. & Debieve, F. HIF1A and EPAS1 potentiate hypoxia-induced upregulation of inhibin alpha chain expression in human term cytotrophoblasts in vitro. Mol. Hum. Reprod. 23, gax002 (2017).L’Hôte, D. et al. Centimorgan-range one-step mapping of fertility traits using interspecific recombinant congenic mice. Genetics 176, 1907–21 (2007).Laissue, P., L’Hôte, D., Serres, C. & Vaiman, D. Mouse models for identifying genes modulating fertility parameters. animal 3, 55 (2009).Laissue, P. et al. Identification of Quantitative Trait Loci responsible for embryonic lethality in mice assessed by ultrasonography. Int. J. Dev. Biol. 53, 623–629 (2009).Quintero-Ronderos, P. et al. THBD sequence variants potentially related to recurrent pregnancy loss. Reprod. Biol. Endocrinol. 15, 92 (2017).Vatin, M. et al. Refined Mapping of a Quantitative Trait Locus on Chromosome 1 Responsible for Mouse Embryonic Death. PLoS One 7, e43356 (2012).Vatin, M. et al. Polymorphisms of human placental alkaline phosphatase are associated with in vitro fertilization success and recurrent pregnancy loss. Am. J. Pathol. 184, 362–368 (2014).L’Hôte, D. et al. Interspecific resources: a major tool for quantitative trait locus cloning and speciation research. BioEssays 32, 132–42 (2010).Guénet, J. L. & Bonhomme, F. Wild mice: an ever-increasing contribution to a popular mammalian model. Trends Genet. 19, 24–31 (2003).Burgio, G. et al. Interspecific Recombinant Congenic Strains Between C57BL/6 and Mice of the Mus spretus Species: A Powerful Tool to Dissect Genetic Control of Complex Traits. Genetics 177, 2321–33 (2007).Quintero-Ronderos, P. & Laissue, P. The multisystemic functions of FOXD1 in development and disease. J. Mol. Med. 96, 725–739 (2018).Feng, J., Liu, T., Qin, B., Zhang, Y. & Liu, X. S. Identifying ChIP-seq enrichment using MACS. Nat. Protoc. 7, 1728–1740 (2012).Zhang, Y. et al. Model-based Analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).He, Q., Johnston, J. & Zeitlinger, J. ChIP-nexus enables improved detection of in vivo transcription factor binding footprints. Nat. Biotechnol. 33, 395–401 (2015).Welch, R. P. et al. Chipenrich: Gene Set Enrichment For ChIP-seq Peak Data. (2017). at <https://bioconductor.org/packages/devel/bioc/vignettes/chipenrich/inst/doc/chipenrich-vignette.html>Liu, T. MACS2 pileup value in xls file. (2014). at <https://groups.google.com/d/msg/macs-announcement/c__KCotHsok/Wp1VdX3XgAUJ>Elemento, O. & Giannopoulou, E. G. ChIP sequencing analysis in R/Bioconductor. (2014). at <http://physiology.med.cornell.edu/faculty/elemento/lab/data/courses/2014/CSHLseq/ChIP-seq.pdf>Sahu, P. Biostars: Bioinformatics explained. (2015). at <https://www.biostars.org/p/198970/#210571>Chow, W.-N. et al. Complement 3 deficiency impairs early pregnancy in mice. Mol. Reprod. Dev. 76, 647–655 (2009).Pham, C. T. & Ley, T. J. Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc. Natl. Acad. Sci. U. S. A. 96, 8627–32 (1999).Adkison, A. M., Raptis, S. Z., Kelley, D. G. & Pham, C. T. N. Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. J. Clin. Invest. 109, 363–371 (2002).Méthot, N. et al. Inhibition of the Activation of Multiple Serine Proteases with a Cathepsin C Inhibitor Requires Sustained Exposure to Prevent Pro-enzyme Processing. J. Biol. Chem. 282, 20836–20846 (2007).Meade, J. L. et al. Proteolytic Activation of the Cytotoxic Phenotype during Human NK Cell Development. J. Immunol. 183, 803–813 (2009).Menkhorst, E. M. et al. Decidual-Secreted Factors Alter Invasive Trophoblast Membrane and Secreted Proteins Implying a Role for Decidual Cell Regulation of Placentation. PLoS One 7, e31418 (2012).Zhu, X.-Y. et al. Blockade of CD86 Signaling Facilitates a Th2 Bias at the Maternal-Fetal Interface and Expands Peripheral CD4+CD25+ Regulatory T Cells to Rescue Abortion-Prone Fetuses1. Biol. Reprod. 72, 338–345 (2005).Wang, J. et al. Vascular endothelial growth factor affects dendritic cell activity in hypertensive disorders of pregnancy. Mol. Med. Rep. 12, 3781–3786 (2015).Whitley, G. S. J. & Cartwright, J. E. Trophoblast-mediated spiral artery remodelling: a role for apoptosis. J. Anat. 215, 21–26 (2009).Khong, T. Y., De Wolf, F., Robertson, W. B. & Brosens, I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br. J. Obstet. Gynaecol. 93, 1049–59 (1986).Urata, H., Kinoshita, A., Misono, K. S., Bumpus, F. M. & Husain, A. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J. Biol. Chem. 265, 22348–57 (1990).Tchougounova, E. et al. A Key Role for Mast Cell Chymase in the Activation of Pro-matrix Metalloprotease-9 and Pro-matrix Metalloprotease-2. J. Biol. Chem. 280, 9291–9296 (2005).Marx, L. et al. Decidual mast cells might be involved in the onset of human first-trimester abortion. Am. J. Reprod. Immunol. 41, 34–40 (1999).Garfield, R. E., Irani, A.-M., Schwartz, L. B., Bytautiene, E. & Romero, R. Structural and functional comparison of mast cells in the pregnant versus nonpregnant human uterus. Am. J. Obstet. Gynecol. 194, 261–267 (2006).Meyer, N. et al. Chymase-producing cells of the innate immune system are required for decidual vascular remodeling and fetal growth. Sci. Rep. 7, 45106 (2017).Clarson, L. H., Roberts, V. H. J., Hamark, B., Elliott, A. C. & Powell, T. Store-operated Ca 2+ entry in first trimester and term human placenta. J. Physiol. 550, 515–528 (2003).Jacobs, B. E., Liu, Y., Pulina, M. V., Golovina, V. A. & Hamlyn, J. M. Normal pregnancy: mechanisms underlying the paradox of a ouabain-resistant state with elevated endogenous ouabain, suppressed arterial sodium calcium exchange, and low blood pressure. Am. J. Physiol. Circ. Physiol. 302, H1317–H1329 (2012).Dykes, I. M. & Emanueli, C. Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA. Genomics. Proteomics Bioinformatics 15, 177–186 (2017).Herriges, M. J. et al. Long noncoding RNAs are spatially correlated with transcription factors and regulate lung development. 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Genómica funcional y disección molecular de FOXD1 para la identificación de nuevos biomarcadores genéticos asociados a patologías de la reproducción de origen endometrial y placentario

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