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Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure

2021-05-07Journal article Restricted access
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dc.contributor.authorHardy, Jimmaline J.
dc.contributor.authorWyrwoll, Margot J.
dc.contributor.authorMcfadden, William
dc.contributor.authorMalcher, Agnieszka
dc.contributor.authorRotte, Nadja
dc.contributor.authorPollock, Nijole C.
dc.contributor.authorMunyoki, Sarah
dc.contributor.authorVeroli, Maria V.
dc.contributor.authorHouston, Brendan J.
dc.contributor.authorXavier, Miguel J.
dc.contributor.authorKasak, Laura
dc.contributor.authorPunab, Margus
dc.contributor.authorLaan, Maris
dc.contributor.authorKliesch, Sabine
dc.contributor.authorSchlegel, Peter
dc.contributor.authorJaffe, Thomas
dc.contributor.authorHwang, Kathleen
dc.contributor.authorVukina, Josip
dc.contributor.authorBrieño-Enríquez, Miguel A.
dc.contributor.authorOrwig, Kyle
dc.contributor.authorYanowitz, Judith
dc.contributor.authorBuszczak, Michael
dc.contributor.authorVeltman, Joris A.
dc.contributor.authorOud, Manon
dc.contributor.authorNagirnaja, Liina
dc.contributor.authorOlszewska, Marta
dc.contributor.authorO’Bryan, Moira K.
dc.contributor.authorConrad, Donald F.
dc.contributor.authorKurpisz, Maciej
dc.contributor.authorTüttelmann, Frank
dc.contributor.authorYatsenko, Alexander N.
dc.contributor.authorConrad, Donald F.
dc.contributor.authorNagirnaja, Liina
dc.contributor.authorAston, Kenneth I.
dc.contributor.authorCarrell, Douglas T.
dc.contributor.authorHotaling, James M.
dc.contributor.authorJenkins, Timothy G.
dc.contributor.authorMcLachlan, Rob
dc.contributor.authorO’Bryan, Moira K.
dc.contributor.authorSchlegel, Peter N.
dc.contributor.authorEisenberg, Michael L.
dc.contributor.authorSandlow, Jay I.
dc.contributor.authorJungheim, Emily S.
dc.contributor.authorOmurtag, Kenan R.
dc.contributor.authorLopes, Alexandra M.
dc.contributor.authorSeixas, Susana
dc.contributor.authorCarvalho, Filipa
dc.contributor.authorFernandes, Susana
dc.contributor.authorBarros, Alberto
dc.contributor.authorGonçalves, João
dc.contributor.authorCaetano, Iris
dc.contributor.authorPinto, Graça
dc.contributor.authorCorreia, Sónia
dc.contributor.authorLaan, Maris
dc.contributor.authorPunab, Margus
dc.contributor.authorMeyts, Ewa Rajpert-De
dc.contributor.authorJørgensen, Niels
dc.contributor.authorAlmstrup, Kristian
dc.contributor.authorKrausz, Csilla G.
dc.contributor.authorJarvi, Keith A.
dc.contributor.authoron behalf of GEMINI Consortium
dc.date.accessioned2022-02-07T16:07:12Z
dc.date.available2022-02-07T16:07:12Z
dc.date.issued2021-05-07
dc.descriptionFree PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266742/pdf/nihms-1705620.pdfpt_PT
dc.descriptionGEMINI Consortium: Donald F Conrad, Liina Nagirnaja, Kenneth I Aston, Douglas T Carrell, James M Hotaling, Timothy G Jenkins, Rob McLachlan, Moira K O'Bryan, Peter N Schlegel, Michael L Eisenberg, Jay I Sandlow, Emily S Jungheim, Kenan R Omurtag, Alexandra M Lopes, Susana Seixas, Filipa Carvalho, Susana Fernandes, Alberto Barros, João Gonçalves, Iris Caetano, Graça Pinto, Sónia Correia, Maris Laan, Margus Punab, Ewa Rajpert-De Meyts, Niels Jørgensen, Kristian Almstrup, Csilla G Krausz, Keith A Jarvi.pt_PT
dc.descriptionMember of GEMINI Consortium: João Gonçalves (INSA), lista completa na pág 1179.pt_PT
dc.description.abstractMale infertility impacts millions of couples yet, the etiology of primary infertility remains largely unknown. A critical element of successful spermatogenesis is maintenance of genome integrity. Here, we present a genomic study of spermatogenic failure (SPGF). Our initial analysis (n=176) did not reveal known gene-candidates but identifed a potentially signifcant single-nucleotide variant (SNV) in X-linked germ-cell nuclear antigen (GCNA). Together with a larger follow-up study (n=2049), 7 likely clinically relevant GCNA variants were identifed. GCNA is critical for genome integrity in male meiosis and knockout models exhibit impaired spermatogenesis and infertility. Single-cell RNA-seq and immunohistochemistry confrm human GCNA expression from spermatogonia to elongated spermatids. Five identifed SNVs were located in key functional regions, including N-terminal SUMO-interacting motif and C-terminal Spartan-like protease domain. Notably, variant p.Ala115ProfsTer7 results in an early frameshift, while Spartan-like domain missense variants p.Ser659Trp and p.Arg664Cys change conserved residues, likely afecting 3D structure. For variants within GCNA’s intrinsically disordered region, we performed computational modeling for consensus motifs. Two SNVs were predicted to impact the structure of these consensus motifs. All identifed variants have an extremely low minor allele frequency in the general population and 6 of 7 were not detected in>5000 biological fathers. Considering evidence from animal models, germ-cell-specifc expression, 3D modeling, and computational predictions for SNVs, we propose that identifed GCNA variants disrupt structure and function of the respective protein domains, ultimately arresting germ-cell division. To our knowledge, this is the frst study implicating GCNA, a key genome integrity factor, in human male infertility.pt_PT
dc.description.sponsorshipThis study was supported by The Eunice Kennedy Shriver NICHD Grant HD080755 (ANY), the Magee-Womens Research Institute University of Pittsburgh Start Up Fund (ANY), PA DoH Grant SAP4100085736 (ANY), NIH P50 Specialized Center Grant HD096723 (KO, ANY, DC, PNS, KH, and MBE), German Research Foundation Clinical Research Unit ‘Male Germ Cells’ grant DFG CRU326 (FT), National Science Centre in Poland, grants no.: 2017/26/D/NZ5/00789 (AM) and 2015/17/B/NZ2/01157; NCN 2020/37/B/NZ5/00549 (MK), Magee-Womens Research Institute University of Pittsburgh, Faculty Fellowship Award and NICHD T32 HD087194 (JH), GM125812 (MB), GM127569 (MB, JLY, and ANY), NIH R00H090289 (MABE), National Health and Medical Research Council Project grant APP1120356 (MKOB, JAV, and DC), UUKi Rutherford Fund Fellowship (BJH), Estonian Research Council, grants IUT34-12 and PRG1021 (ML), and The Netherlands Organization for Scientifc Research grant no.: 918-15-667 as well as an Investigator Award in Science from the Wellcome Trust grant no.: 209451 (JAV). Computational analysis was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationHum Genet. 2021 Aug;140(8):1169-1182. doi: 10.1007/s00439-021-02287-y. Epub 2021 May 7.pt_PT
dc.identifier.doi10.1007/s00439-021-02287-ypt_PT
dc.identifier.issn0340-6717
dc.identifier.urihttp://hdl.handle.net/10400.18/7938
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringerpt_PT
dc.relation.publisherversionhttps://link.springer.com/article/10.1007/s00439-021-02287-ypt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectMale Infertilitypt_PT
dc.subjectGCNApt_PT
dc.subjectSpermatogenic Failurept_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleVariants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failurept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage1182pt_PT
oaire.citation.issue8pt_PT
oaire.citation.startPage1169pt_PT
oaire.citation.titleHuman Geneticspt_PT
oaire.citation.volume140pt_PT
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT

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