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A genetic variant in the 3′-UTR of PIWIL4 confers risk for extreme phenotypes of male infertility by altering miR-215 and miR-136 binding affinity

2025-06-11Artigo científico Acesso aberto
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datacite.subject.fosCiências Médicas
datacite.subject.sdg03:Saúde de Qualidade
dc.contributor.authorGonzález-Muñoz, Sara
dc.contributor.authorCerván-Martín, Miriam
dc.contributor.authorGuzmán-Jiménez, Andrea
dc.contributor.authorRodríguez-Martín, Ana Isabel
dc.contributor.authorGarrido, Nicolás
dc.contributor.authorCastilla, José A.
dc.contributor.authorGonzalvo, M. Carmen
dc.contributor.authorClavero, Ana
dc.contributor.authorMolina, Marta
dc.contributor.authorVilches, Miguel Ángel
dc.contributor.authorEspuch-Oliver, Andrea
dc.contributor.authorMaldonado, Vicente
dc.contributor.authorGarcía-Peña, María Luisa
dc.contributor.authorGaliano-Gutiérrez, Noelia
dc.contributor.authorSantamaría, Esther
dc.contributor.authorGonzález, Cristina
dc.contributor.authorQuintana-Ferraz, Fernando
dc.contributor.authorGómez, Susana
dc.contributor.authorAmorós, David
dc.contributor.authorMartínez-Granados, Luis
dc.contributor.authorOrtega-González, Yanira
dc.contributor.authorBurgos, Miguel
dc.contributor.authorPereira-Caetano, Iris
dc.contributor.authorPinto, Graça S.
dc.contributor.authorAguiar, Ana
dc.contributor.authorPereira, Isabel S.
dc.contributor.authorLópez-Rodrigo, Olga
dc.contributor.authorBassas, Lluís
dc.contributor.authorSeixas, Susana
dc.contributor.authorGonçalves, João
dc.contributor.authorLopes, Alexandra M.
dc.contributor.authorLarriba, Sara
dc.contributor.authorBossini-Castillo, Lara
dc.contributor.authorCarmona, F. David
dc.contributor.authorPalomino-Morales, Rogelio J.
dc.date.accessioned2026-01-27T13:04:33Z
dc.date.available2026-01-27T13:04:33Z
dc.date.issued2025-06-11
dc.descriptionErratum in: Hum Reprod. 2025 Sep 1;40(9):1797. doi: 10.1093/humrep/deaf142
dc.description.abstractStudy question: What is the functional impact of the rs508485 genetic polymorphism, located in the 3'-untranslated region (UTR) region of the PIWIL4 gene, on non-obstructive azoospermia (NOA)? Summary answer: The rs508485 genetic variant contributes to the pathogenesis of extreme patterns of NOA by modulating PIWIL4 expression through microRNA (miRNA) interactions. What is known already: Male infertility represents a significant global health challenge with profound societal and economic consequences. One of the most severe forms of male infertility is NOA, which is characterized by severe spermatogenic failure (SPGF) of idiopathic origin in most cases. Cumulating knowledge increasingly suggests that this idiopathic form of NOA may represent a multifactorial condition involving complex interactions between genetic and environmental factors. The PIWI protein subfamily, particularly PIWIL4, plays a pivotal role in spermatogenesis by processing PIWI-interacting RNAs, which silence retrotransposons to protect genomic integrity. Genetic variations in this gene have been found to be associated with susceptibility to NOA. Study design, size, duration: A case-control study was conducted in a European cohort including 1516 infertile men with SPGF and 2451 fertile controls. Logistic regression and functional assays were employed to investigate the functional role of the rs508485 polymorphism in PIWIL4. Participants/materials, setting, methods: Participants were genotyped for the rs508485 polymorphism. Associations between the polymorphism and NOA phenotypes, including Sertoli cell-only (SCO) syndrome and testicular sperm extraction (TESE) outcomes, were assessed. In silico tools predicted miRNA binding effects, which were subsequently validated using luciferase reporter assays. Main results and the role of chance: The T allele of rs508485 was significantly associated with the SCO phenotype (P = 2.69E-03, OR = 1.34) and unfavourable TESE outcomes (P = 1.09E-03, OR = 1.54). In silico analyses predicted that the rs508485 variant might alter binding sites in the 3'-UTR region of PIWIL4 for different miRNAs, such as hsa-miR-215-3p and hsa-miR-136-3p. Functional validation using luciferase assays confirmed that these miRNAs differentially bind to the T and C alleles of this polymorphism, influencing PIWIL4 regulation. Large scale data: N/A. Limitations, reasons for caution: The study is limited to a single genetic polymorphism and functional assays were performed in vitro. Additional studies are required to validate these findings across diverse populations and explore additional genetic interactions. Wider implications of the findings: These findings highlight the critical role of miRNA regulation in extreme forms of male infertility by influencing the expression of essential spermatogenesis genes, such as PIWIL4. Our study sheds light on the genetic mechanisms underlying spermatogenesis and suggests potential therapeutic targets for NOA.eng
dc.description.sponsorshipThis work was supported by the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (grant: PID2020-120157RB-I00 funded by MICIU/AEI/10.13039/501100011033; and grant: PID2023-152215OB-I00 funded by MICIU/AEI/10.13039/501100011033 and ERDF, EU). M. C.-M is beneficiary of a Juan de la Cierva 2022 postdoctoral fellowship (reference number JDC2022-048561-I) funded by MCIN/AEI/10.13039/501100011033 and European Union NextGenerationEU/PRTR. S.L. received support from “Generalitat de Catalunya” (grant 2021SGR052). S.L. is sponsored by the “Researchers Consolidation Program” from the SNS-Dpt. Salut Generalitat de Catalunya (Exp. CES09/020). S.G.-M. was funded by grant ref. FPU23/02674. S.S. was supported by funds from the Portuguese Foundation for Science and Technology (FCT; 10.54499/DL57/2016/CP1363/CT0019).
dc.identifier.citationHum Reprod . 2025 Sep 1;40(9):1762-1772. doi: 10.1093/humrep/deaf107
dc.identifier.doi10.1093/humrep/deaf107
dc.identifier.eissn1460-2350
dc.identifier.issn0268-1161
dc.identifier.pmid40499151
dc.identifier.urihttp://hdl.handle.net/10400.18/10765
dc.language.isoeng
dc.peerreviewedyes
dc.publisherOxford University Press
dc.relation10.54499/DL57/2016/CP1363/CT0019
dc.relation.hasversionhttps://academic.oup.com/humrep/article/40/9/1762/8160611
dc.relation.ispartofHuman Reproduction
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectNOA
dc.subjectSCO
dc.subjectTESE
dc.subjectPIWIL4
dc.subjectpiRNA
dc.subjectmiRNA
dc.subjectSNP
dc.subjectMale Infertility
dc.subjectDoenças Genéticas
dc.titleA genetic variant in the 3′-UTR of PIWIL4 confers risk for extreme phenotypes of male infertility by altering miR-215 and miR-136 binding affinityeng
dc.typejournal article
dcterms.referenceshttps://academic.oup.com/humrep/article/40/9/1762/8160611?login=true#supplementary-data
dspace.entity.typePublication
oaire.citation.endPage1772
oaire.citation.issue9
oaire.citation.startPage1762
oaire.citation.titleHuman Reproduction
oaire.citation.volume40
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85

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