Novel genes and mutations in patients affected by recurrent pregnancy loss

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. © 2017 Quintero-Ronderos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

• Fecha de publicación: 2017
• Institución: Universidad del Rosario
• Repositorio: Repositorio EdocUR - U. Rosario
• Idioma: eng
• OAI Identifier: oai:repository.urosario.edu.co:10336/19029
• Acceso en línea: https://doi.org/10.1371/journal.pone.0186149; http://repository.urosario.edu.co/handle/10336/19029
• Palabra clave: Fibrinógeno; Secundario; Estromelisina 2; Habitual; Humano; Molecular; Fibrinógeno Alphac; Proteína Mmp1; Fragmento de péptido; Gen Adams1; Amn gen; Bioinformática; Gen Bmp7; Caucásico; Gen Cdh1; Gen Cdh11; Artículo Clínico; Gen Col6A3; Gen Cr1; Modificación de ADN; Gen Epas1; Gen F5; Gen Fga; Gen Fgfr2; Gen Flt1; Gen; Función del gen; Mutación genética; Secuencia de genes; Código genético; Estabilidad Genética; Variabilidad genética; Variación genética; Gen Ido2; Gen lifr; Gen Mmp1; Gen Mmp9; Gen Ncoa1; Secuenciación de próxima generación; Fenotipo; Aborto Recurrente; Secuenciación de Sangre; Gen Thbd; Gen Tlr3; Gen Tnc; Gen Traf3Ip1; Creer gen; Secuenciación del exoma completo; Aborto; Biología; Química; Exoma; La expresión génica; Genética; Genotipo; Secuenciación de alto rendimiento; Metabolismo; Modelo molecular; Mutación; Fisiopatología; El embarazo; Dominio de proteínas; Estructura secundaria de proteínas; Teoría cuántica; Termodinámica; Biología Computacional; Secuenciación de nucleótidos de alto rendimiento; Matriz metaloproteinasa 1; Modelos; Fragmentos de péptidos; Dominios y motivos de interacción de proteínas; Estructura de la proteína; Enfermedades; Tro Gene; Protein Structure; Peptide Fragments; Protein Interaction Domains And Motifs; Matrix Metalloproteinase 1; Humans; Models; Computational Biology; High-Throughput Nucleotide Sequencing; Thermodynamics; Quantum Theory; Protein Secondary Structure; Protein Domain; Pregnancy; Pathophysiology; Mutation; Molecular Model; Metabolism; High Throughput Sequencing; Genotype; Genetics; Gene Expression; Exome; Chemistry; Biology; Abortion; Whole Exome Sequencing; Traf3Ip1 Gene; Tlr3 Gene; Thbd Gene; Sanger Sequencing; Recurrent Abortion; Phenotype; Next Generation Sequencing; Ncoa1 Gene; Mmp1 Gene; Mmp9 Gene; Lifr Gene; Ido2 Gene; Genetic Variation; Genetic Variability; Genetic Code; Genetic Stability; Gene Sequence; Gene Mutation; Gene Function; Gene; Flt1 Gene; Fgfr2 Gene; F5 Gene; Fga Gene; Dna Modification; Epas1 Gene; Cr1 Gene; Col6A3 Gene; Clinical Article; Cdh11 Gene; Cdh1 Gene; Caucasian; Bmp7 Gene; Amn Gene; Bioinformatics; Adamts1 Gene; Peptide Fragment; Mmp1 Protein; Fibrinogen Alphac; Human; Stromelysin 2; Secondary; Fibrinogen; Enfermedades del aparato genital; Infertilidad; Reproducción
• License: Abierto (Texto Completo)