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Common genetic variation in KATNAL1 non‐coding regions is involved in the susceptibility to severe phenotypes of male infertility

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dc.contributor.authorCerván‐Martín, Miriam
dc.contributor.authorBossini‐Castillo, Lara
dc.contributor.authorGuzmán‐Jiménez, Andrea
dc.contributor.authorRivera‐Egea, Rocío
dc.contributor.authorGarrido, Nicolás
dc.contributor.authorLujan, Saturnino
dc.contributor.authorRomeu, Gema
dc.contributor.authorSantos-Ribeiro, Samuel
dc.contributor.authorCastilla, José Antonio
dc.contributor.authorGonzalvo, María del Carmen
dc.contributor.authorClavero, Ana
dc.contributor.authorMaldonado, Vicente
dc.contributor.authorVicente, Francisco Javier
dc.contributor.authorBurgos, Miguel
dc.contributor.authorJiménez, Rafael
dc.contributor.authorGonzález‐Muñoz, Sara
dc.contributor.authorSánchez‐Curbelo, Josvany
dc.contributor.authorLópez‐Rodrigo, Olga
dc.contributor.authorPereira‐Caetano, Iris
dc.contributor.authorMarques, Patricia Isabel
dc.contributor.authorCarvalho, Filipa
dc.contributor.authorBarros, Alberto
dc.contributor.authorBassas, Lluís
dc.contributor.authorSeixas, Susana
dc.contributor.authorGonçalves, João
dc.contributor.authorLarriba, Sara
dc.contributor.authorLopes, Alexandra Manuel
dc.contributor.authorPalomino‐Morales, Rogelio Jesús
dc.contributor.authorCarmona, Francisco David
dc.date.accessioned2022-09-19T14:56:27Z
dc.date.available2022-09-19T14:56:27Z
dc.date.issued2022
dc.description© 2022 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.pt_PT
dc.description.abstractBackground: Previous studies in animal models evidenced that genetic mutations of KATNAL1, resulting in dysfunction of its encoded protein, lead to male infertility through disruption of microtubule remodelling and premature germ cell exfoliation. Subsequent studies in humans also suggested a possible role of KATNAL1 single-nucleotide polymorphisms in the development of male infertility as a consequence of severe spermatogenic failure. Objectives: The main objective of the present study is to evaluate the effect of the common genetic variation of KATNAL1 in a large and phenotypically well-characterised cohort of infertile men because of severe spermatogenic failure. Materials and methods: A total of 715 infertile men because of severe spermatogenic failure, including 210 severe oligospermia and 505 non-obstructive azoospermia patients, as well as 1058 unaffected controls were genotyped for three KATNAL1 single-nucleotide polymorphism taggers (rs2077011, rs7338931 and rs2149971). Case-control association analyses by logistic regression assuming different models and in silico functional characterisation of risk variants were conducted. Results: Genetic associations were observed between the three analysed taggers and different severe spermatogenic failure groups. However, in all cases, the haplotype model (rs2077011*C | rs7338931*T | rs2149971*A) better explained the observed associations than the three risk alleles independently. This haplotype was associated with non-obstructive azoospermia (adjusted p = 4.96E-02, odds ratio = 2.97), Sertoli-cell only syndrome (adjusted p = 2.83E-02, odds ratio = 5.16) and testicular sperm extraction unsuccessful outcomes (adjusted p = 8.99E-04, odds ratio = 6.13). The in silico analyses indicated that the effect on severe spermatogenic failure predisposition could be because of an alteration of the KATNAL1 splicing pattern. Conclusions: Specific allelic combinations of KATNAL1 genetic polymorphisms may confer a risk of developing severe male infertility phenotypes by favouring the overrepresentation of a short non-functional transcript isoform in the testis.pt_PT
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 (refs. SAF2016-78722-R and PID2020-120157RB-I00), the ‘Instituto de Salud Carlos III’ (Fondo de Investigaciones Sanitarias)/Fondo Europeo de Desarrollo Regional ‘Una manera de hacer Europa’ (FIS/FEDER) (ref. DTS18/00101 to Sara Larriba), the Generalitat de Catalunya (ref. 2017SGR191), the ‘Ramón y Cajal’ program (ref. RYC-2014-16458) and the ‘Juan de la Cierva Incorporación’ program (ref. IJC2018-038026-I), as well as the Andalusian Government through the R&D&i Projects Grants for Universities and Public Research Entities (ref. PY20_00212), which include FEDER funds. Andrea Guzmán-Jiménez was a recipient of a grant from the Spanish Ministry of Education and Professional Training (‘Becas de Colaboración en Departamentos Universitarios para el curso académico 2020/2021’). Patricia I. Marques is supported by the FCT post-doctoral fellowship (SFRH/BPD/120777/2016), financed from the Portuguese State Budget of the Ministry for Science, Technology and High Education and from the European Social Fund, available through the ‘Programa Operacional do Capital Humano’. João Gonçalves was partially funded by FCT/MCTES through national funds attributed to the Centre for Toxicogenomics and Human Health—ToxOmics (UID/BIM/00009/2016 and UIDB/00009/2020). Sara Larriba is sponsored by the Researchers Consolidation Program (ISCIII SNS/Dpt. Salut Generalitat de Catalunya) (CES09/020).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAndrology. 2022 Oct;10(7):1339-1350pt_PT
dc.identifier.doi10.1111/andr.13221pt_PT
dc.identifier.eissn2047-2927
dc.identifier.issn2047-2919
dc.identifier.urihttp://hdl.handle.net/10451/54503
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relationUID/BIM/00009/2016pt_PT
dc.relationUnderstanding the basis of semen hyperviscosity and asthenozoospermia phenotypes - a systems biology approach
dc.relationCentre for Toxicogenomics and Human Health
dc.relation.publisherversionhttps://onlinelibrary.wiley.com/journal/20472927pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.subjectKATNAL1pt_PT
dc.subjectSNPpt_PT
dc.subjectMale infertilitypt_PT
dc.subjectSpermatogenesispt_PT
dc.subjectSplicingpt_PT
dc.titleCommon genetic variation in KATNAL1 non‐coding regions is involved in the susceptibility to severe phenotypes of male infertilitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberSFRH/BPD/120777/2016
oaire.awardNumberUIDB/00009/2020
oaire.awardTitleUnderstanding the basis of semen hyperviscosity and asthenozoospermia phenotypes - a systems biology approach
oaire.awardTitleCentre for Toxicogenomics and Human Health
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F120777%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00009%2F2020/PT
oaire.citation.endPage1350pt_PT
oaire.citation.issue7pt_PT
oaire.citation.startPage1339pt_PT
oaire.citation.titleAndrologypt_PT
oaire.citation.volume10pt_PT
oaire.fundingStream6817 - DCRRNI ID
person.familyNameSantos-Ribeiro
person.givenNameSamuel
person.identifier.ciencia-id321F-CBA7-5BA0
person.identifier.orcid0000-0003-2476-7858
person.identifier.ridQ-1203-2017
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication20396650-6f92-4c35-af41-6f9151cea2ff
relation.isAuthorOfPublication.latestForDiscovery20396650-6f92-4c35-af41-6f9151cea2ff
relation.isProjectOfPublicationad14fc64-1a0d-4812-a48b-e08eef73bd35
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