Whole-exome sequencing and Drosophila modelling reveal mutated genes and pathways contributing to human ovarian failure
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Le résumé fourni par la source
BACKGROUND: Ovarian failure (OF) is a multifactorial, complex disease presented by up to 1% of women under 40 years of age. Despite 90% of patients being diagnosed with idiopathic OF, the underlying molecular mechanisms remain unknown, making it difficult to personalize treatments for these patients in the clinical setting. Studying the presence and/or accumulation of SNVs at the gene/pathway levels will help describe novel genes and characterize disrupted biological pathways linked with ovarian failure. METHODS: Ad-hoc case-control SNV screening conducted from 2020 to 2023 of 150 VCF files WES data included Spanish IVF patients with (n = 118) and without (n = 32) OF (< 40 years of age; mean BMI 22.78) along with GnomAD (n = 38,947) and IGSR (n = 1,271; 258 European female VCF) data for pseudo-control female populations. SNVs were prioritized according to their predicted deleteriousness, frequency in genomic databases, and proportional differences across populations. A burden test was performed to reveal genes with a higher presence of SNVs in the OF cohort in comparison to control and pseudo-control groups. Systematic in-silico analyses were performed to assess the potential disruptions caused by the mutated genes in relevant biological pathways. Finally, genes with orthologues in Drosophila melanogaster were considered to experimentally validate the potential impediments to ovarian function and reproductive potential. RESULTS: Eighteen genes had a higher presence of SNVs in the OF population (FDR < 0.05). AK2, CDC27, CFTR, CTBP2, KMT2C, and MTCH2 were associated with OF for the first time and their silenced/knockout forms reduced fertility in Drosophila. We also predicted the disruption of 29 sub-pathways across four signalling pathways (FDR < 0.05). These sub-pathways included the metaphase to anaphase transition during oocyte meiosis, inflammatory processes related to necroptosis, DNA repair mismatch systems and the MAPK signalling cascade. CONCLUSIONS: This study sheds light on the underlying molecular mechanisms of OF, providing novel associations for six genes and OF-related infertility, setting a foundation for further biomarker development, and improving precision medicine in infertility.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Whole-exome sequencing and Drosophila modelling reveal mutated genes and pathways contributing to human ovarian failure
- Date Crossref
- 04/12/2024
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Universitat de València pays non établi dans la noticeUniversité ou école supérieure
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Instituto de Investigación Sanitaria La Fe pays non établi dans la noticeOrganisation à but non lucratif
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IVIRMA Global pays non établi dans la noticeÉtablissement de santé
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Universidad Europea de Valencia pays non établi dans la noticeUniversité ou école supérieure
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University of Cambridge High-Performance Computing Service pays non établi dans la noticeUniversité ou école supérieure
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University of Valencia Department of Pediatrics pays non établi dans la noticeUniversité ou école supérieure
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IVI Foundation IVI-RMA Global Research Alliance pays non établi dans la noticeOrganisation à but non lucratif
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Faculty of Health Sciences Department of Physiotherapy pays non établi dans la noticeUniversité ou école supérieure
Universitat de València, Instituto de Investigación Sanitaria La Fe et IVIRMA Global, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.