Bi-allelic missense variants in MEI4 cause preimplantation embryonic arrest and female infertility

AbstractPreimplantation embryonic arrest is an important pathogenesis of female infertility, but little is known about the genetic factors behind this phenotype. MEI4 is an essential protein for DNA double-strand break formation during meiosis, andMei4 knock-out female mice are viable but sterile, indicating that MEI4 plays a crucial role in reproduction. To date,MEI4 has not been found to be associated with any human reproductive diseases. Here, we identified six compound heterozygous and homozygousMEI4 variants —namely, c.293C >  T, p.(Ser98Leu), c.401C >  G, p.(Pro134Arg), c.391C >  G, p.(Pro131Ala), c.914A >  T, p.(Tyr305Phe), c.908C >  G, p.(Ala303Gly), and c.899A >  T, p.(Gln300Leu)—in four independent families that were responsible for female infertility mainly characterized by preimplantation embryonic arrest. In vitro, we found that these variants reduced the interaction between MEI4 and DNA. In vivo, we generated a knock-in mouse model and demonstrated that female mice were infertile and were characterized by developmental defects during oogenesis. Our findings reveal the important roles ofMEI4 in human reproduction and provide a new diagnostic marker for genetic counseling of clinical infertility patients.
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research