Novel genes and mutations in patients affected by recurrent pregnancy loss

Título traducido de la contribución: Nuevos genes y mutaciones en pacientes afectadas por la pérdida recurrente del embarazo

Paula Quintero-Ronderos, Eric Mercier, Michiko Fukuda, Ronald González, Carlos Fernando Suárez, Manuel Alfonso Patarroyo, Daniel Vaiman, Jean-Christophe Gris, Paul Laissue

Resultado de la investigación: Contribución a una revistaArtículo

12 Citas (Scopus)

Resumen

La pérdida recurrente de embarazos es una enfermedad relacionada con la infertilidad humana que se presenta con frecuencia y que afecta a ~1% de las mujeres. Se ha estimado que la causa sigue siendo inexplicable en más del 50% de los casos, lo que sugiere fuertemente que los factores genéticos pueden contribuir al fenotipo. En cuanto a su etiología molecular, numerosos estudios han tenido un éxito limitado en la identificación de las causas genéticas de la enfermedad. Esto podría deberse al hecho de que cientos de genes están involucrados en cada paso fisiológico necesario para garantizar el éxito reproductivo de los mamíferos. En tal escenario, la secuenciación de la próxima generación proporciona una herramienta potencialmente interesante para la investigación de las mutaciones causantes de la pérdida recurrente del embarazo.

El presente estudio incluyó la secuenciación del exoma completo y un innovador análisis bioinformático, por primera vez, en 49 mujeres no relacionadas afectadas por la pérdida recurrente de embarazos. Se identificaron 27 variantes de codificación (22 genes) potencialmente relacionadas con el fenotipo (41% de los pacientes). Los genes afectados, que fueron enriquecidos por variantes de secuencia potencialmente deletéreas, pertenecían a cascadas moleculares distintas que desempeñaban un papel clave en la biología de la implantación y el embarazo.

Usando un método de enfoque de química cuántica establecimos que las mutaciones en las proteínas MMP-10 y FGA llevaron a modificaciones energéticas sustanciales que sugieren un impacto en sus funciones y/o estabilidad.

Los enfoques de secuenciación y bioinformática de próxima generación presentados aquí representan una forma eficaz de encontrar mutaciones, con efectos funcionales potencialmente moderados/fuertes, asociados con la etiología de la pérdida recurrente del embarazo. Consideramos que algunas de estas variantes (y genes) representan probables biomarcadores futuros para la pérdida recurrente del embarazo.
Idioma originalInglés estadounidense
Páginas (desde-hasta)e0186149
PublicaciónPLoS One
Volumen12
N.º10
DOI
EstadoPublicada - 2017
Publicado de forma externa

Citar esto

Quintero-Ronderos, P., Mercier, E., Fukuda, M., González, R., Suárez, C. F., Patarroyo, M. A., ... Laissue, P. (2017). Novel genes and mutations in patients affected by recurrent pregnancy loss. PLoS One, 12(10), e0186149. https://doi.org/10.1371/journal.pone.0186149
Quintero-Ronderos, Paula ; Mercier, Eric ; Fukuda, Michiko ; González, Ronald ; Suárez, Carlos Fernando ; Patarroyo, Manuel Alfonso ; Vaiman, Daniel ; Gris, Jean-Christophe ; Laissue, Paul. / Novel genes and mutations in patients affected by recurrent pregnancy loss. En: PLoS One. 2017 ; Vol. 12, N.º 10. pp. e0186149.
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abstract = "Recurrent pregnancy loss is a frequently occurring human infertility-related disease affecting ~1{\%} of women. It has been estimated that the cause remains unexplained in >50{\%} cases which strongly suggests that genetic factors may contribute towards the phenotype. Concerning its molecular aetiology numerous studies have had limited success in identifying the disease's genetic causes. This might have been due to the fact that hundreds of genes are involved in each physiological step necessary for guaranteeing reproductive success in mammals. In such scenario, next generation sequencing provides a potentially interesting tool for research into recurrent pregnancy loss causative mutations. The present study involved whole-exome sequencing and an innovative bioinformatics analysis, for the first time, in 49 unrelated women affected by recurrent pregnancy loss. We identified 27 coding variants (22 genes) potentially related to the phenotype (41{\%} of patients). The affected genes, which were enriched by potentially deleterious sequence variants, belonged to distinct molecular cascades playing key roles in implantation/pregnancy biology. Using a quantum chemical approach method we established that mutations in MMP-10 and FGA proteins led to substantial energetic modifications suggesting an impact on their functions and/or stability. The next generation sequencing and bioinformatics approaches presented here represent an efficient way to find mutations, having potentially moderate/strong functional effects, associated with recurrent pregnancy loss aetiology. We consider that some of these variants (and genes) represent probable future biomarkers for recurrent pregnancy loss.",
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Quintero-Ronderos, P, Mercier, E, Fukuda, M, González, R, Suárez, CF, Patarroyo, MA, Vaiman, D, Gris, J-C & Laissue, P 2017, 'Novel genes and mutations in patients affected by recurrent pregnancy loss', PLoS One, vol. 12, n.º 10, pp. e0186149. https://doi.org/10.1371/journal.pone.0186149

Novel genes and mutations in patients affected by recurrent pregnancy loss. / Quintero-Ronderos, Paula; Mercier, Eric; Fukuda, Michiko; González, Ronald; Suárez, Carlos Fernando; Patarroyo, Manuel Alfonso; Vaiman, Daniel; Gris, Jean-Christophe; Laissue, Paul.

En: PLoS One, Vol. 12, N.º 10, 2017, p. e0186149.

Resultado de la investigación: Contribución a una revistaArtículo

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AU - Mercier, Eric

AU - Fukuda, Michiko

AU - González, Ronald

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AU - Patarroyo, Manuel Alfonso

AU - Vaiman, Daniel

AU - Gris, Jean-Christophe

AU - Laissue, Paul

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N2 - Recurrent pregnancy loss is a frequently occurring human infertility-related disease affecting ~1% of women. It has been estimated that the cause remains unexplained in >50% cases which strongly suggests that genetic factors may contribute towards the phenotype. Concerning its molecular aetiology numerous studies have had limited success in identifying the disease's genetic causes. This might have been due to the fact that hundreds of genes are involved in each physiological step necessary for guaranteeing reproductive success in mammals. In such scenario, next generation sequencing provides a potentially interesting tool for research into recurrent pregnancy loss causative mutations. The present study involved whole-exome sequencing and an innovative bioinformatics analysis, for the first time, in 49 unrelated women affected by recurrent pregnancy loss. We identified 27 coding variants (22 genes) potentially related to the phenotype (41% of patients). The affected genes, which were enriched by potentially deleterious sequence variants, belonged to distinct molecular cascades playing key roles in implantation/pregnancy biology. Using a quantum chemical approach method we established that mutations in MMP-10 and FGA proteins led to substantial energetic modifications suggesting an impact on their functions and/or stability. The next generation sequencing and bioinformatics approaches presented here represent an efficient way to find mutations, having potentially moderate/strong functional effects, associated with recurrent pregnancy loss aetiology. We consider that some of these variants (and genes) represent probable future biomarkers for recurrent pregnancy loss.

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VL - 12

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JO - PLoS One

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SN - 1932-6203

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Quintero-Ronderos P, Mercier E, Fukuda M, González R, Suárez CF, Patarroyo MA y otros. Novel genes and mutations in patients affected by recurrent pregnancy loss. PLoS One. 2017;12(10):e0186149. https://doi.org/10.1371/journal.pone.0186149