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Rare double sex and mab-3-related transcription factor 1 regulatory variants in severe spermatogenic failure

2015-09Journal article Restricted access
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dc.contributor.authorLima, A.C.
dc.contributor.authorCarvalho, F.
dc.contributor.authorGonçalves, J.
dc.contributor.authorFernandes, S.
dc.contributor.authorMarques, P.I.
dc.contributor.authorSousa, M.
dc.contributor.authorBarros, A.
dc.contributor.authorSeixas, A.
dc.contributor.authorAmorim, A.
dc.contributor.authorConrad, D.F.
dc.contributor.authorLopes, M.
dc.date.accessioned2016-02-18T13:45:12Z
dc.date.available2016-10-01T00:30:09Z
dc.date.issued2015-09
dc.description.abstractThe double sex and mab-3-related transcription factor 1 (DMRT1) gene has long been linked to sex-determining pathways across vertebrates and is known to play an essential role in gonadal development and maintenance of spermatogenesis in mice. In humans, the genomic region harboring the DMRT gene cluster has been implicated in disorders of sex development and recently DMRT1 deletions were shown to be associated with non-obstructive azoospermia (NOA). In this work, we have employed different methods to screen a cohort of Portuguese NOA patients for DMRT1 exonic insertions and deletions [by multiplex ligation probe assay (MLPA); n = 68] and point mutations (by Sanger sequencing; n = 155). We have found three novel patient-specific non-coding variants in heterozygosity that were absent from 357 geographically matched controls. One of these is a complex variant with a putative regulatory role (c.-223_-219CGAAA>T), located in the promoter region within a conserved sequence involved in Dmrt1 repression. Moreover, while DMRT1 domains are highly conserved across vertebrates and show reduced levels of diversity in human populations, two rare synonymous substitutions (rs376518776 and rs34946058) and two rare non-coding variants that potentially affect DMRT1 expression and splicing (rs144122237 and rs200423545) were overrepresented in patients when compared with 376 Portuguese controls (301 fertile and 75 normozoospermic). Overall our previous and present results suggest a role of changes in DMRT1 dosage in NOA potentially also through a process of gene misregulation, even though DMRT1 deleterious variants seem to be rare.pt_PT
dc.description.sponsorshipThis work was partially funded by the Portuguese Foundation for Science and Technology FCT/MCTES (PIDDAC) and co-financed by European Funds (FEDER) through the COMPETE program (PTDC/SAU-GMG/101229/2008 to AML), CIGMH and Pest-OE/SAU/UI00009/2011. IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology, and Higher Education and is partially supported by FCT. AML and ACL are funded by FCT fellowships SFRH/BPD/73366/2010 and SFRH/BD/51695/2011, respectively. DFC was supported by grant number R01HD078641 from the Eunice Kennedy Shriver National Institute of Child Health and Development of the United States National Institutes of Health.pt_PT
dc.identifier.citationAndrology. 2015 Sep;3(5):825-33. doi: 10.1111/andr.12063. Epub 2015 Jul 2.pt_PT
dc.identifier.doi10.1111/andr.12063pt_PT
dc.identifier.issn2047-2919
dc.identifier.urihttp://hdl.handle.net/10400.18/3400
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Society of Andrology and European Academy of Andrologypt_PT
dc.relation.publisherversionhttp://onlinelibrary.wiley.com/doi/10.1111/andr.12063/fullpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectDMRT1pt_PT
dc.subjectMale Infertilitypt_PT
dc.subjectAzoospermiapt_PT
dc.subjectSpermatogenic Failurept_PT
dc.subjectAlternative Splicingpt_PT
dc.subjectcis-regulatory Variantspt_PT
dc.subjectDouble Sex and mab-3-related Transcription Factor 1pt_PT
dc.subjectDouble Sex and mab-3-related Transcription Factor 1 promoterpt_PT
dc.subjectNon-obstructive Azoospermiapt_PT
dc.titleRare double sex and mab-3-related transcription factor 1 regulatory variants in severe spermatogenic failurept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FSAU-GMG%2F101229%2F2008/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/PEst-OE%2FSAU%2FUI4013%2F2014/PT
oaire.citation.endPage833pt_PT
oaire.citation.startPage825pt_PT
oaire.citation.titleAndrologypt_PT
oaire.citation.volume3(5)pt_PT
oaire.fundingStream5876-PPCDTI
oaire.fundingStream5876
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.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicationb2892b8f-387e-4216-9064-792937959b05
relation.isProjectOfPublicationc9ff07db-6fe7-4f77-b74c-12eb478486e6
relation.isProjectOfPublication.latestForDiscoveryb2892b8f-387e-4216-9064-792937959b05

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