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Biallelic mutations in M1AP are associated with meiotic arrest, severely impaired spermatogenesis and male infertility

2020-06Conference object Open access
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dc.contributor.authorFriedrich, C.
dc.contributor.authorTemel, S.G.
dc.contributor.authorNagirnaja, L.
dc.contributor.authorOud, M.S.
dc.contributor.authorLopes, A.M.
dc.contributor.authorvan der Heijden, G.W.
dc.contributor.authorHeald, J.
dc.contributor.authorRotte, N.
dc.contributor.authorHeald, J.
dc.contributor.authorRotte, N.
dc.contributor.authorWistuba, J.
dc.contributor.authorWöste, M.
dc.contributor.authorLedig, S.
dc.contributor.authorKrenz, H.
dc.contributor.authorSmits, R.M.
dc.contributor.authorCarvalho, F.
dc.contributor.authorGonçalves, João
dc.contributor.authorFietz, D.
dc.contributor.authorTürkgenç, B.
dc.contributor.authorErgören, M.C.
dc.contributor.authorÇetinkaya, M.
dc.contributor.authorBaşar, M.
dc.contributor.authorKahraman, S.
dc.contributor.authorMcEleny, K.
dc.contributor.authorXavier, M.J.
dc.contributor.authorTurner, H.
dc.contributor.authorPilatz, A.
dc.contributor.authorRöpke, A.
dc.contributor.authorDugas, M.
dc.contributor.authorKliesch, S.
dc.contributor.authorNeuhaus, N.
dc.contributor.authorGEMINI Consortium
dc.contributor.authorAston, K.I.
dc.contributor.authorConrad, D.F.
dc.contributor.authorVeltman, J.A.
dc.contributor.authorWyrwoll, M.J.
dc.contributor.authorTüttelmann, F.
dc.date.accessioned2021-03-13T15:14:07Z
dc.date.available2021-03-13T15:14:07Z
dc.date.issued2020-06
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, but so far only few validated causal genes have been reported. To address this gap, we performed whole exome sequencing in 58 men with unexplained meiotic arrest and identified in three unrelated men the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 arresting protein. This variant results in a truncated protein lacking 57% of its full-length as shown in vitro by heterologous expression of mutated M1AP. Next, we screened four large cohorts of 1904 infertile men from the International Male Infertility Genomics Consortium (IMIGC) and identified three additional cases carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP. Moreover, a homozygous missense variant p.(Pro389Leu) segregated with infertility in five men from a consanguineous Turkish family (LOD score = 3.28). 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 was described for mice with disruption of M1ap. Collectively, these findings demonstrate that mutations in M1AP cause autosomal recessive severe spermatogenic failure and male infertility. In view of the evidences from several independent groups and populations, M1AP should be included in the growing list of validated male infertility genes.pt_PT
dc.description.sponsorshipThis work was supported by DFG Clinical Research Unit “Male Germ Cells: from Genes to Function” (CRU326).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationEur J Hum Genet. 2020 Dec;28(Suppl 1):1002-1003.pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/7444
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relation.publisherversionhttps://www.nature.com/articles/s41431-020-00741-5pt_PT
dc.subjectAzoospermiapt_PT
dc.subjectM1APpt_PT
dc.subjectMale Infertilitypt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleBiallelic mutations in M1AP are associated with meiotic arrest, severely impaired spermatogenesis and male infertilitypt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferencePlace(online)pt_PT
oaire.citation.endPage1003pt_PT
oaire.citation.issueSuppl 1pt_PT
oaire.citation.startPage1002pt_PT
oaire.citation.title53rd European Society of Human Genetics (ESHG) Conference, 6-9 june 2020pt_PT
oaire.citation.volume28pt_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.rightsopenAccesspt_PT
rcaap.typeconferenceObjectpt_PT
relation.isAuthorOfPublication6bbd19e6-ea9c-4502-b972-ec6997e9c481
relation.isAuthorOfPublication.latestForDiscovery6bbd19e6-ea9c-4502-b972-ec6997e9c481

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