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Diminished DNA binding affinity of DMRT1 caused by heterozygous DM domain mutations is a cause of male infertility

2025-01-08Artigo científico Acesso aberto
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datacite.subject.fosCiências Médicas
datacite.subject.sdg03:Saúde de Qualidade
dc.contributor.authorMarić, Tihana
dc.contributor.authorCastillo-Madeen, Helen
dc.contributor.authorKlarić, Monika Logara
dc.contributor.authorBarišić, Antun
dc.contributor.authorTrgovec-Greif, Lovro
dc.contributor.authorMurphy, Mark W.
dc.contributor.authorJuchnewitsch, Anna-Grete
dc.contributor.authorLillepea, Kristiina
dc.contributor.authorDutta, Avirup
dc.contributor.authorŽunić, Lucija
dc.contributor.authorStendahl, Alexandra M.
dc.contributor.authorPunab, Margus
dc.contributor.authorPomm, Kristjan
dc.contributor.authorMendoza, Daniel M.
dc.contributor.authorLopes, Alexandra M.
dc.contributor.authorŠorgić, Ana Merkler
dc.contributor.authorVugrek, Oliver
dc.contributor.authorGonçalves, João
dc.contributor.authorAlmstrup, Kristian
dc.contributor.authorAston, Kenneth I.
dc.contributor.authorBelužić, Robert
dc.contributor.authorJežek, Davor
dc.contributor.authorBertoša, Branimir
dc.contributor.authorLaan, Maris
dc.contributor.authorBojanac, Ana Katušić
dc.contributor.authorConrad, Donald F.
dc.contributor.authorBarbalić, Maja
dc.date.accessioned2026-01-27T13:15:19Z
dc.date.available2026-01-27T13:15:19Z
dc.date.issued2025-01-08
dc.description.abstractThe most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome sequencing in the Croatian infertile brothers with NOA and found a variant in DMRT1 (Doublesex and mab-3 related transcription factor 1) gene that was further assessed by the EMSA assay and molecular dynamic simulations. We additionally screened for DMRT1 mutations in 1940 infertile men diagnosed with spermatogenic failure, 644 normozoospermic controls, and 105 females with primary ovarian insufficiency (POI) recruited to the GEnetics of Male INfertility Initiative (GEMINI) or Estonian Andrology (ESTAND) cohorts. DMRT1 p.Pro74Leu (chr9:g.842059C > T) variant was detected in infertile brothers in the highly conserved position within the DNA binding DM domain of the protein. EMSA assay showed reduced DNA binding of DMRT1P74L and molecular dynamic simulations showed differences in structural and dynamical properties between the wild type protein and DMRT1P74L. Plausible disease-causing DMRT1 variants were only identified in infertile men (13/1940; 0.67%), and none in 639 fertile controls. Burden testing showed an excess of rare deleterious DM domain mutations in the infertility cohort compared to gnomAD v.4.0 population-based controls (Fisher’s exact test, p = 1.44 x 10−5). Three rare deleterious variants in DMRT1 were found in 104 cases of POI. The findings of this study strengthen the evidence of DMRT1 variants being a causal factor for male infertility and provide the distribution of likely pathogenic variants across the gene. This is also the first study to suggest that DMRT1 variants may also be linked to POI.eng
dc.description.sponsorshipCroatian study was supported by Scientific Center of Excellence for Reproductive and Regenerative Medicine, Republic of Croatia, and funded by the EU through European Regional Devel-opment Fund under: GrantNo.KK.01.1.1.01.0008 — Reproductive and Regenerative Medicine — Exploring New Platforms and Potentials” and “Development and strengthening of research and inno-vation capacities, and application advanced technologies” and grant No.KK.01.2.1.01.0113, while also supported by COST (European Cooperation in Science and Technology, https://www.cost.eu/) under‘ANDRONETCA20119 COST Action. U S National Institutes of Healthgrant GM127379. The GEMINI study is funded by US National Institutes of Health grants R01HD078641 and P50HD096723. The ESTAND study is supported by the Estonian Research Council Grant number PRG1021 to ML
dc.identifier.citationHum Mol Genet. 2025 Mar 7;34(6):481-491. doi: 10.1093/hmg/ddae197. Epub 2025 Jan 8
dc.identifier.doi10.1093/hmg/ddae197
dc.identifier.eissn1460-2083
dc.identifier.issn0964-6906
dc.identifier.pmid39777458
dc.identifier.urihttp://hdl.handle.net/10400.18/10766
dc.language.isoeng
dc.peerreviewedyes
dc.publisherOxford University Press
dc.relation.hasversionhttps://academic.oup.com/hmg/article/34/6/481/7945157
dc.relation.ispartofHuman Molecular Genetics
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectDMRT1
dc.subjectExome Sequencing
dc.subjectAzoospermia
dc.subjectInfertility
dc.subjectGenetics
dc.subjectDoenças Genéticas
dc.titleDiminished DNA binding affinity of DMRT1 caused by heterozygous DM domain mutations is a cause of male infertilityeng
dc.typejournal article
dcterms.referenceshttps://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/hmg/34/6/10.1093_hmg_ddae197/1/supplementary_table_3_ddae197.docx?Expires=1772535365&Signature=BpGGLLXCSAmANxN8~O79RWSgQ-NyHzVROaYEokbYbdEVWOCfkwRrFQ6tnF-hUS~Fou5r6guHR7mI~fR0~l7OMV-NQFgNRmM6NY58YpSD1UHS1CVLHc2RcjWB6LlEJYj8SU~smKXn1GmuLEjjzonepjHmFnuKvk28ENQ8zkE7GfZcGq3q0XUvRQQW5UyvOaaKIX8EIHP7AM5T7EAitIF2N0C-5PEjXBbpn11bfbf5gQVD1guRn0icoMu7NHabNrJKNfL~mC5dXlxdKmLD7q0o6vUXLIs9E5FWzFCy9oxr-d5a0uiwwUKNqu8a2tWF7RGj7aqnSfzTaZDnqz1pJUvphg__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA
dcterms.referenceshttps://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/hmg/34/6/10.1093_hmg_ddae197/1/maricetal_supplementaryinformation_ddae197.docx?Expires=1772535365&Signature=1AOM4ECrDV~T-ScBE-f008anOnoYFDTRy288WymSgQxyy9GrbBn-c3Dp7WhCeoNWVWM~wTPZmOWfEYGP6oz4YkwLzGXhHRH8BVkck-5A5d4TqrbbYgnYk68gdKbr79DSMI1W3-9wZWI~dR1z7SEcdy30ZpMIeG~nHMRwp2vc2X6qfvqiRJH~XDz4ufYIO3v4-UJ3bc2y~PovEVQRLf6pxtuYBADo7dOUfY2~BkERPTX-L~o8avBHjY98zEIVygsP7zZnDc0rMztrvUpG-6q2J~X73nLgkKOpWzV3Be2QIhkSB0NFdC6Ai8KJb9br3KqC6oBoVmudplon8~iv3KfCkQ__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA
dspace.entity.typePublication
oaire.citation.endPage491
oaire.citation.issue6
oaire.citation.startPage481
oaire.citation.titleHuman Molecular Genetics
oaire.citation.volume34
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85

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