A de novo paradigm for male infertility.

Autor: Oud MS; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands., Smits RM; Department of Obstetrics and Gynaecology, Radboudumc, Nijmegen, The Netherlands., Smith HE; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Mastrorosa FK; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Holt GS; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Houston BJ; School of BioSciences, Faculty of Science, The University of Melbourne, Parkville, VIC, Australia., de Vries PF; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands., Alobaidi BKS; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Batty LE; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Ismail H; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Greenwood J; Department of Genetic Medicine, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Sheth H; Foundation for Research in Genetics and Endocrinology, Institute of Human Genetics, Ahmedabad, India., Mikulasova A; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Astuti GDN; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.; Division of Human Genetics, Center for Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indonesia., Gilissen C; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands., McEleny K; Newcastle Fertility Centre, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Turner H; Department of Cellular Pathology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Coxhead J; Genomics Core Facility, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Cockell S; Bioinformatics Support Unit, Faculty of Medical Sciences New, castle University, Newcastle upon Tyne, UK., Braat DDM; Department of Obstetrics and Gynaecology, Radboudumc, Nijmegen, The Netherlands., Fleischer K; Department of Obstetrics and Gynaecology, Radboudumc, Nijmegen, The Netherlands., D'Hauwers KWM; Department of Urology, Radboudumc, Nijmegen, The Netherlands., Schaafsma E; Department of Pathology, Radboudumc, Nijmegen, The Netherlands., Nagirnaja L; Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA., Conrad DF; Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA., Friedrich C; Institute of Reproductive Genetics, University of Münster, Münster, Germany., Kliesch S; Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster, Münster, Germany., Aston KI; Department of Surgery, Division of Urology, University of Utah School of Medicine, Salt Lake City, UT, USA., Riera-Escamilla A; Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Barcelona, Catalonia, Spain., Krausz C; Department of Biomedical, Experimental and Clinical Sciences 'Mario Serio', University of Florence, Florence, Italy., Gonzaga-Jauregui C; Regeneron Genetics Center, Tarrytown, NY, USA., Santibanez-Koref M; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Elliott DJ; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., Vissers LELM; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands., Tüttelmann F; Institute of Reproductive Genetics, University of Münster, Münster, Germany., O'Bryan MK; School of BioSciences, Faculty of Science, The University of Melbourne, Parkville, VIC, Australia., Ramos L; Department of Obstetrics and Gynaecology, Radboudumc, Nijmegen, The Netherlands., Xavier MJ; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK., van der Heijden GW; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands.; Department of Obstetrics and Gynaecology, Radboudumc, Nijmegen, The Netherlands., Veltman JA; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. joris.veltman@newcastle.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jan 10; Vol. 13 (1), pp. 154. Date of Electronic Publication: 2022 Jan 10.
DOI: 10.1038/s41467-021-27132-8
Abstrakt: De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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