We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10-5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10-4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.
A de novo paradigm for male infertility / Oud M.S.; Smits R.M.; Smith H.E.; Mastrorosa F.K.; Holt G.S.; Houston B.J.; de Vries P.F.; Alobaidi B.K.S.; Batty L.E.; Ismail H.; Greenwood J.; Sheth H.; Mikulasova A.; Astuti G.D.N.; Gilissen C.; McEleny K.; Turner H.; Coxhead J.; Cockell S.; Braat D.D.M.; Fleischer K.; D'Hauwers K.W.M.; Schaafsma E.; Conrad D.F.; Nagirnaja L.; Aston K.I.; Carrell D.T.; Hotaling J.M.; Jenkins T.G.; McLachlan R.; O'Bryan M.K.; Schlegel P.N.; Eisenberg M.L.; Sandlow J.I.; Jungheim E.S.; Omurtag K.R.; Lopes A.M.; Seixas S.; Carvalho F.; Fernandes S.; Barros A.; Goncalves J.; Caetano I.; Pinto G.; Correia S.; Laan M.; Punab M.; Meyts E.R.-D.; Jorgensen N.; Almstrup K.; Krausz C.G.; Jarvi K.A.; Nagirnaja L.; Conrad D.F.; Friedrich C.; Kliesch S.; Riera-Escamilla A.; Gonzaga-Jauregui C.; Santibanez-Koref M.; Elliott D.J.; Vissers L.E.L.M.; Tuttelmann F.; Ramos L.; Xavier M.J.; van der Heijden G.W.; Veltman J.A.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - STAMPA. - 13:(2022), pp. 154-164. [10.1038/s41467-021-27132-8]
A de novo paradigm for male infertility
Krausz C. G.;
2022
Abstract
We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10-5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10-4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.
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