Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Biallelic mutations in M1AP are a frequent cause of meiotic arrest leading to male infertility

Margot J. Wyrwoll, Şehime G. Temel, Liina Nagirnaja, Manon S. Oud, Alexandra M. Lopes, Godfried W. van der Heijden, Nadja Rotte, Joachim Wistuba, Marius Wöste, Susanne Ledig, Henrike Krenz, Roos M. Smits, Filipa Carvalho, João Gonçalves, Daniela Fietz, Burcu Türkgenç, Mahmut C. Ergören, Murat Çetinkaya, Murad Başar, Semra Kahraman, Adrian Pilatz, Albrecht Röpke, Martin Dugas, Sabine Kliesch, Nina Neuhaus, GEMINI Consortium, Kenneth I. Aston, View ORCID ProfileDonald F. Conrad, Joris A. Veltman, Corinna Friedrich, View ORCID ProfileFrank Tüttelmann
doi: https://doi.org/10.1101/803346
Margot J. Wyrwoll
1Institute of Human Genetics, University of Münster, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Şehime G. Temel
2Bursa Uludag University, Faculty of Medicine, Department of Medical Genetics & Department of Histology & Embryology & Health Sciences Institute, Department of Translational Medicine, Bursa, Turkey
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Liina Nagirnaja
3Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Portland, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Manon S. Oud
4Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alexandra M. Lopes
5Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal
6Instituto de Investigação e Inovação em Saúde (i3s), Universidade do Porto, Porto, Portugal
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Godfried W. van der Heijden
4Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
7Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nadja Rotte
8Centre of Reproductive Medicine and Andrology, Institute of Reproductive Medicine, University of Münster, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joachim Wistuba
8Centre of Reproductive Medicine and Andrology, Institute of Reproductive Medicine, University of Münster, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marius Wöste
9Institute of Medical Informatics, University of Münster, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susanne Ledig
1Institute of Human Genetics, University of Münster, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Henrike Krenz
9Institute of Medical Informatics, University of Münster, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Roos M. Smits
7Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Filipa Carvalho
10Serviço de Genética, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
João Gonçalves
11Dep. de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniela Fietz
12Institute of Veterinary Anatomy, Histology and Embryology, Justus Liebig University, Gießen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Burcu Türkgenç
13University of Acibadem, Acibadem Genetic Diagnostic Centre, Istanbul, Turkey
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mahmut C. Ergören
14Near East University, Faculty of Medicine, Department of Medical Biology, Nicosia, Cyprus
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Murat Çetinkaya
15Istanbul Memorial Hospital, Assisted Reproductive Technologies and Reproductive Genetics Centre, Istanbul, Turkey
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Murad Başar
16Istanbul Memorial Hospital, Department of Urology & Andrology, Istanbul, Turkey
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Semra Kahraman
17Istanbul Memorial Hospital, Assisted Reproductive Technologies and Reproductive Genetics, Istanbul, Turkey
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adrian Pilatz
18Clinic for Urology, Pediatric Urology and Andrology, Justus Liebig University, Gießen, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Albrecht Röpke
1Institute of Human Genetics, University of Münster, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Martin Dugas
9Institute of Medical Informatics, University of Münster, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sabine Kliesch
19Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nina Neuhaus
8Centre of Reproductive Medicine and Andrology, Institute of Reproductive Medicine, University of Münster, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kenneth I. Aston
20Andrology and IVF Laboratories, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Donald F. Conrad
3Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Portland, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Donald F. Conrad
Joris A. Veltman
4Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands
21Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Corinna Friedrich
1Institute of Human Genetics, University of Münster, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Frank Tüttelmann
1Institute of Human Genetics, University of Münster, Münster, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Frank Tüttelmann
  • For correspondence: frank.tuettelmann@ukmuenster.de
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Male infertility affects ∼7% of men in Western societies, but its causes remain poorly understood. The most clinically severe form of male infertility is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis, but so far only few genes have been reported to cause germ cell arrest in males. To address this gap, whole exome sequencing was performed in 60 German men with complete meiotic arrest, and we identified in three unrelated men the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP, encoding meiosis 1 arresting protein. Then, with collaborators from the International Male Infertility Genomics Consortium (IMIGC), we screened a Dutch cohort comprising 99 infertile men and detected the same homozygous variant c.676dup in a man with hypospermatogenesis predominantly displaying meiotic arrest. We also identified two Portuguese men with NOA carrying likely biallelic loss-of-function (LoF) and missense variants in M1AP among men screened by the Genetics of Male Infertility Initiative (GEMINI). Moreover, we discovered a homozygous missense variant p.(Pro389Leu) in M1AP in a consanguineous Turkish family comprising five infertile men. M1AP is predominantly expressed in human and mouse spermatogonia up to secondary spermatocytes and previous studies have shown that knockout male mice are infertile due to meiotic arrest. Collectively, these findings demonstrate that both LoF and missense M1AP variants that impair its protein cause autosomal-recessive meiotic arrest, non-obstructive azoospermia and male infertility. In view of the evidence from several independent groups and populations, M1AP should be included in the growing list of validated NOA genes.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted October 15, 2019.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Biallelic mutations in M1AP are a frequent cause of meiotic arrest leading to male infertility
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Biallelic mutations in M1AP are a frequent cause of meiotic arrest leading to male infertility
Margot J. Wyrwoll, Şehime G. Temel, Liina Nagirnaja, Manon S. Oud, Alexandra M. Lopes, Godfried W. van der Heijden, Nadja Rotte, Joachim Wistuba, Marius Wöste, Susanne Ledig, Henrike Krenz, Roos M. Smits, Filipa Carvalho, João Gonçalves, Daniela Fietz, Burcu Türkgenç, Mahmut C. Ergören, Murat Çetinkaya, Murad Başar, Semra Kahraman, Adrian Pilatz, Albrecht Röpke, Martin Dugas, Sabine Kliesch, Nina Neuhaus, GEMINI Consortium, Kenneth I. Aston, Donald F. Conrad, Joris A. Veltman, Corinna Friedrich, Frank Tüttelmann
bioRxiv 803346; doi: https://doi.org/10.1101/803346
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Biallelic mutations in M1AP are a frequent cause of meiotic arrest leading to male infertility
Margot J. Wyrwoll, Şehime G. Temel, Liina Nagirnaja, Manon S. Oud, Alexandra M. Lopes, Godfried W. van der Heijden, Nadja Rotte, Joachim Wistuba, Marius Wöste, Susanne Ledig, Henrike Krenz, Roos M. Smits, Filipa Carvalho, João Gonçalves, Daniela Fietz, Burcu Türkgenç, Mahmut C. Ergören, Murat Çetinkaya, Murad Başar, Semra Kahraman, Adrian Pilatz, Albrecht Röpke, Martin Dugas, Sabine Kliesch, Nina Neuhaus, GEMINI Consortium, Kenneth I. Aston, Donald F. Conrad, Joris A. Veltman, Corinna Friedrich, Frank Tüttelmann
bioRxiv 803346; doi: https://doi.org/10.1101/803346

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genetics
Subject Areas
All Articles
  • Animal Behavior and Cognition (2530)
  • Biochemistry (4972)
  • Bioengineering (3482)
  • Bioinformatics (15212)
  • Biophysics (6897)
  • Cancer Biology (5390)
  • Cell Biology (7738)
  • Clinical Trials (138)
  • Developmental Biology (4530)
  • Ecology (7147)
  • Epidemiology (2059)
  • Evolutionary Biology (10227)
  • Genetics (7512)
  • Genomics (9786)
  • Immunology (4844)
  • Microbiology (13215)
  • Molecular Biology (5138)
  • Neuroscience (29435)
  • Paleontology (203)
  • Pathology (837)
  • Pharmacology and Toxicology (1463)
  • Physiology (2138)
  • Plant Biology (4748)
  • Scientific Communication and Education (1013)
  • Synthetic Biology (1338)
  • Systems Biology (4012)
  • Zoology (768)