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<p>Male infertility has been linked to M1AP. In mice, M1AP interacts with the ZZS proteins SHOC1/TEX11/SPO16, promoting DNA class I crossover formation during meiosis. To determine whether M1AP and ZZS proteins are involved in human male infertility by recombination failure, we screened for biallelic/hemizygous loss-of-function (LoF) variants in the human genes to select men with presumed protein deficiency (<i>N</i> = 24). After in-depth characterisation of testicular phenotypes, we identified gene-specific meiotic impairments: men with ZZS deficiency shared an early meiotic arrest. Men with LoF variants in <i>M1AP</i> exhibited a predominant metaphase I arrest with rare haploid round or even elongated spermatids. These differences were explained by different recombination failures: deficient ZZS function led to incorrect synapsis of homologous chromosomes, unrepaired DNA double-strand breaks, and incomplete recombination. Abolished M1AP led to a reduced number of recombination intermediates and class I crossover. Medically assisted reproduction resulted in the birth of a healthy child, offering the possibility of fatherhood to men with LoF variants in <i>M1AP</i>. Our study establishes M1AP as an important, but non-essential, functional enhancer in meiotic recombination.</p>

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Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月15日

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  • Nadja Rotte,
  • Jessica E M Dunleavy,
  • Michelle D Runkel,
  • Lina Bosse,
  • Daniela Fietz,
  • Adrian Pilatz,
  • Johanna Kuss,
  • Ann-Kristin Dicke,
  • Sofia B Winge,
  • Sara Di Persio,
  • Christian Ruckert,
  • Verena Nordhoff,
  • Hans-Christian Schuppe,
  • Kristian Almstrup,
  • Sabine Kliesch,
  • Nina Neuhaus,
  • Birgit Stallmeyer,
  • Moira K O’Bryan,
  • Frank Tüttelmann,
  • Corinna Friedrich

摘要

Male infertility has been linked to M1AP. In mice, M1AP interacts with the ZZS proteins SHOC1/TEX11/SPO16, promoting DNA class I crossover formation during meiosis. To determine whether M1AP and ZZS proteins are involved in human male infertility by recombination failure, we screened for biallelic/hemizygous loss-of-function (LoF) variants in the human genes to select men with presumed protein deficiency (N = 24). After in-depth characterisation of testicular phenotypes, we identified gene-specific meiotic impairments: men with ZZS deficiency shared an early meiotic arrest. Men with LoF variants in M1AP exhibited a predominant metaphase I arrest with rare haploid round or even elongated spermatids. These differences were explained by different recombination failures: deficient ZZS function led to incorrect synapsis of homologous chromosomes, unrepaired DNA double-strand breaks, and incomplete recombination. Abolished M1AP led to a reduced number of recombination intermediates and class I crossover. Medically assisted reproduction resulted in the birth of a healthy child, offering the possibility of fatherhood to men with LoF variants in M1AP. Our study establishes M1AP as an important, but non-essential, functional enhancer in meiotic recombination.