Repository logo
 
Publication

Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility

2020-08-06Journal article Restricted access
Simple item page
dc.contributor.authorWyrwoll, Margot J.
dc.contributor.authorTemel, Şehime G.
dc.contributor.authorNagirnaja, Liina
dc.contributor.authorOud, Manon S.
dc.contributor.authorLopes, Alexandra M.
dc.contributor.authorvan der Heijden, Godfried W.
dc.contributor.authorHeald, James S.
dc.contributor.authorRotte, Nadja
dc.contributor.authorWistuba, Joachim
dc.contributor.authorWöste, Marius
dc.contributor.authorLedig, Susanne
dc.contributor.authorKrenz, Henrike
dc.contributor.authorSmits, Roos M.
dc.contributor.authorCarvalho, Filipa
dc.contributor.authorGonçalves, João
dc.contributor.authorFietz, Daniela
dc.contributor.authorTürkgenç, Burcu
dc.contributor.authorErgören, Mahmut C.
dc.contributor.authorÇetinkaya, Murat
dc.contributor.authorBaşar, Murad
dc.contributor.authorKahraman, Semra
dc.contributor.authorMcEleny, Kevin
dc.contributor.authorXavier, Miguel J.
dc.contributor.authorTurner, Helen
dc.contributor.authorPilatz, Adrian
dc.contributor.authorRöpke, Albrecht
dc.contributor.authorDugas, Martin
dc.contributor.authorKliesch, Sabine
dc.contributor.authorNeuhaus, Nina
dc.contributor.authorAston, Kenneth I.
dc.contributor.authorConrad, Donald F.
dc.contributor.authorVeltman, Joris A.
dc.contributor.authorFriedrich, Corinna
dc.contributor.authorTüttelmann, Frank
dc.date.accessioned2021-03-07T16:36:21Z
dc.date.available2021-03-07T16:36:21Z
dc.date.issued2020-08-06
dc.description.abstractMale infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 associated protein, in three unrelated men. This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP. Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family. The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed. A similar phenotype has been described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity.pt_PT
dc.description.sponsorshipThis work was carried out within the frame of the German Research Foundation Clinical Research Unit ‘‘Male Germ Cells: from Genes to Function’’ (DFG CRU326). Funding for sequencing of the GEMINI cohort was provided by the National Institutes of Health, United States (R01HD078641). The analyses in the Turkish family were supported by a grant from the Bursa University of Uludag Project Unit [KUAP(T)-2014/36].pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAm J Hum Genet. 2020 Aug 6;107(2):342-351. doi: 10.1016/j.ajhg.2020.06.010. Epub 2020 Jul 15.pt_PT
dc.identifier.doi10.1016/j.ajhg.2020.06.010pt_PT
dc.identifier.issn0002-9297
dc.identifier.urihttp://hdl.handle.net/10400.18/7354
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherCell Presspt_PT
dc.relation.publisherversionhttps://www.cell.com/ajhg/fulltext/S0002-9297(20)30198-1pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAzoospermiapt_PT
dc.subjectCell Cycle Checkpointspt_PT
dc.subjectMaleI Infertilitypt_PT
dc.subjectNon-obstructive azoospermia (NOA)pt_PT
dc.subjectPhenotypept_PT
dc.subjectSpermatogenesispt_PT
dc.subjectSpermatozoapt_PT
dc.subjectM1APpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleBi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertilitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage351pt_PT
oaire.citation.issue2pt_PT
oaire.citation.startPage342pt_PT
oaire.citation.titleAmerican Journal of Human Genetics (AJHG)pt_PT
oaire.citation.volume107pt_PT
person.familyNameGonçalves
person.givenNameJoão
person.identifier.ciencia-id5710-1FAE-5FAB
person.identifier.orcid0000-0001-9359-8774
person.identifier.ridL-2265-2014
person.identifier.scopus-author-id55934387500
rcaap.embargofctAcesso de acordo com página web do editor da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication6bbd19e6-ea9c-4502-b972-ec6997e9c481
relation.isAuthorOfPublication.latestForDiscovery6bbd19e6-ea9c-4502-b972-ec6997e9c481

Files

Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
Wyrwoll et al 2020_M1AP and male infertility.pdf
Size:
1.96 MB
Format:
Adobe Portable Document Format
Download

Collections

DGH - Artigos em revistas internacionais