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

Margot J. Wyrwoll, Şehime G. Temel, Liina Nagirnaja, Manon S. Oud, Alexandra M. Lopes, Godfried W. van der Heijden, James S. Heald, 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 BaşarSemra Kahraman, Kevin McEleny, Miguel J. Xavier, Helen Turner, Adrian Pilatz, Albrecht Röpke, Martin Dugas, Sabine Kliesch, Nina Neuhaus, Kenneth I. Aston, Donald F. Conrad, Joris A. Veltman, Corinna Friedrich, Frank Tüttelmann

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)342-351
Number of pages10
JournalAmerican journal of human genetics
Issue number2
Publication statusPublished - 6 Aug 2020


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


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