Mouse modeling of familial human SYCE1 c.197-2A>G splice site mutation leads to meiotic recombination failure and non-obstructive azoospermia.

Infertility affects a considerable number of couples at reproductive age, with an incidence of 10-15%. Approximately 25% of cases are classified as idiopathic infertility. Often, errors during the meiotic stage appear to be related to idiopathic infertility. A crucial component during the first meiotic prophase is the synaptonemal complex (SC), which plays a fundamental role in homologous chromosome pairing and meiotic recombination. In many studies with infertile patients, mutations affecting SC-coding genes have been identified. The generation of humanized models has high physiological relevance, helping to clarify the molecular bases of pathology, which in turn is essential for the development of therapeutic procedures. Here, we report the generation and characterization of genetically modified mice carrying a mutation equivalent to SYCE1 c.197-2A>G, previously found in male infertile patients, aiming to determine the actual effects of this mutation on reproductive capacity and to study the underlying molecular mechanisms. Homozygous mutants were infertile. SYCE1 protein was not detected and Syce1 transcript presented minimal levels, suggesting transcript degradation underlying the infertility mechanism. Additionally, homozygous mutants showed impaired homologous chromosome synapsis, meiotic arrest before the pachytene stage, and increased apoptosis of meiotic cells. This study validates the variant as pathogenic and causative of infertility, since the observed dramatic phenotype was attributable to this single homozygous point mutation, when compared to WT and heterozygous littermates. Moreover, although this homozygous point mutation has been only found in infertile men thus far, we anticipate that if it were present in women, it would cause infertility as well, as homozygous female mice also exhibited an infertility phenotype.