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

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

  • Am J Hum Genet. 2020 Aug 6;107(2):342-351. doi: 10.1016/j.ajhg.2020.06.010.
Margot J Wyrwoll 1,  Şehime G Temel 2,  Liina Nagirnaja 3,  Manon S Oud 4,  Alexandra M Lopes 5,  Godfried W van der Heijden 6,  James S Heald 7,  Nadja Rotte 8,  Joachim Wistuba 9,  Marius Wöste 10,  Susanne Ledig 1,  Henrike Krenz 10,  Roos M Smits 11,  Filipa Carvalho 12,  João Gonçalves 13,  Daniela Fietz 14,  Burcu Türkgenç 15,  Mahmut C Ergören 16,  Murat Çetinkaya 17,  Murad Başar 18,  Semra Kahraman 19,  Kevin McEleny 20,  Miguel J Xavier 7,  Helen Turner 21,  Adrian Pilatz 22,  Albrecht Röpke 1,  Martin Dugas 10,  Sabine Kliesch 23,  Nina Neuhaus 9,  GEMINI Consortium,  Kenneth I Aston 24,  Donald F Conrad 3,  Joris A Veltman 25,  Corinna Friedrich 1,  Frank Tüttelmann 26
Affiliations

Affiliations

  • 1 Institute of Human Genetics, University of Münster, 48149 Münster, Germany.
  • 2 Bursa Uludag University, Faculty of Medicine, Department of Medical Genetics & Department of Histology & Embryology & Health Sciences Institute, Department of Translational Medicine, 16059 Bursa, Turkey.
  • 3 Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA.
  • 4 Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
  • 5 Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-804 Porto, Portugal; Instituto de Investigação e Inovação em Saúde (i3s), Universidade do Porto, 4099-002 Porto, Portugal.
  • 6 Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 Nijmegen, the Netherlands; Department of Obstetrics and Gynecology, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
  • 7 Biosciences Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
  • 8 Institute of Human Genetics, University of Münster, 48149 Münster, Germany; Centre of Reproductive Medicine and Andrology, Institute of Reproductive Medicine, University of Münster, 48149 Münster, Germany.
  • 9 Centre of Reproductive Medicine and Andrology, Institute of Reproductive Medicine, University of Münster, 48149 Münster, Germany.
  • 10 Institute of Medical Informatics, University of Münster, 48149 Münster, Germany.
  • 11 Department of Obstetrics and Gynecology, Radboud University Medical Center, 6525 Nijmegen, the Netherlands.
  • 12 Instituto de Investigação e Inovação em Saúde (i3s), Universidade do Porto, 4099-002 Porto, Portugal; Serviço de Genética, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, 4099-002 Porto, Portugal.
  • 13 Departmento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, 1649-016 Lisboa, Portugal; ToxOmics - Centro de Toxicogenómica e Saúde Humana, Nova Medical School, 1169-056 Lisboa, Portugal.
  • 14 Institute of Veterinary Anatomy, Histology and Embryology, Justus Liebig University, 35392 Gießen, Germany.
  • 15 University of Acibadem, Acibadem Genetic Diagnostic Centre, 34662 Istanbul, Turkey.
  • 16 Near East University, Faculty of Medicine, Department of Medical Biology, 99138 Nicosia, Cyprus.
  • 17 Istanbul Memorial Hospital, Assisted Reproductive Technologies and Reproductive Genetics Centre, 34385 Istanbul, Turkey.
  • 18 Istanbul Memorial Hospital, Department of Urology & Andrology, 34385 Istanbul, Turkey.
  • 19 Istanbul Memorial Hospital, Assisted Reproductive Technologies and Reproductive Genetics, 34385 Istanbul, Turkey.
  • 20 Newcastle Fertility Centre, The Newcastle upon Tyne Hospitals NHS Foundation Trust, NE1 4EP Newcastle upon Tyne, UK.
  • 21 Department of Cellular Pathology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, NE1 4LP Newcastle upon Tyne, UK.
  • 22 Clinic for Urology, Pediatric Urology and Andrology, Justus Liebig University, 35392 Gießen, Germany.
  • 23 Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster, 48149 Münster, Germany.
  • 24 Andrology and IVF Laboratories, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
  • 25 Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 Nijmegen, the Netherlands; Biosciences Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
  • 26 Institute of Human Genetics, University of Münster, 48149 Münster, Germany. Electronic address: [email protected].
PMID: 32673564 DOI: 10.1016/j.ajhg.2020.06.010
Abstract

Male 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.

Keywords

M1AP; cryptozoospermia; male infertility; meiosis 1 associated protein; meiotic arrest; non-obstructive azoospermia; oligozoospermia; spermatogenesis; spermatogenic failure.

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