GMNN mutations cause female infertility characterized by preimplantation embryo arrest through regulating DNA re-replication.

Preimplantation embryo arrest is a common cause of female infertility and recurrent failure of assisted reproductive technology. However, its genetic basis is largely unrevealed. Geminin, encoded by the GMNN gene, plays an important role in preventing DNA re-replication by inhibiting CDT1. Here, using whole-exome sequencing and Sanger sequencing, we identified three rare missense mutations of GMNN in females with preimplantation arrest, following a dominant inheritance pattern. The RNA sequencing data from both the mouse zygotes and the patient's one-cell embryo demonstrated the altered cell cycle processes. We then found that these mutations decreased the binding with CDT1 and resulted in activation of CHK1 and DNA damage, resulting in cell cycle disturbance. Our findings uncover a mechanistic understanding of the pathogenesis of human preimplantation embryo arrest, which acts by impairing the correct cell cycle and DNA re-replication procedure, and provides a new molecular target for the diagnosis and treatment of infertile patients.