DLGAP5 mutations disrupt normal chromosome segregation and spindle formation of human oocyte meiosis and lead to female infertility

This study is led by Prof. Lei Jin and Dr. Lixia Zhu (Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology). Assisted reproductive technology (ART) constitutes one of the most effective measures to address the infertility. Recently, the advent of whole‐exome sequencing (WES) has led to the identification of an increasing number of genetic causes of human infertility. However, the genetic underpinnings of a significant proportion of cases remain enigmatic. "it is imperative to elucidate the potential genetic determinants of ART failure and to identify novel genetic etiologies for genetic counseling, as well as for the diagnosis and treatment of infertility patients" Jin says.

Jin and Zhu, together with Meng Wang, a postdoctoral researcher at Tongji Hospital, sought to identify novel genetic causes responsible for human oocyte maturation abnormality and female infertility. The team enrolled intertitle patients who underwent in vitro fertilization/ intracytoplasmic sperm injection. WES was recommended for patients who exhibited oocyte maturation arrest, which was identified as a majority of oocytes retrieved was immature at germinal vesicle (GV) or/and metaphase I stage.

The team identified a novel homozygous nonsense mutation in DLGAP5 in three infertile females from two families. In the oocytes from proband of family 1, the expression of DLGAP5 was absent. The spindle morphology was found to be abnormal, and the chromosomes were poorly aligned, irrespective of the oocyte stage. Although the MII oocytes can be fertilized successfully through IVF, the developmental potential of the embryos was impaired, with no cleavage embryos developing into blastocysts. Additionally, there were fragmented nuclei in the blastomeres of the affected embryos, which were with abnormal karyotypes using whole‐embryo karyotype sequencing. "Utilizing WES, for the first time, we have identified DLGAP5 as a pathogenic gene responsible for human female infertility with phenotype, characterized by abnormal oocyte maturation and embryo development.," Zhu says.

To further validate the previous results, the team collected human GV oocytes and microinjected the oocytes with DLGAP5 siRNAs. The oocytes microinjected with si‐DLGAP5 exhibited significantly oocyte maturation arrest. Moreover, the expression of DLGAP5 was significantly reduced in oocytes in the DLGAP5 siRNA injection group, and the typical morphology of the spindle microtubules was absent with the disarrangement of the chromosomes.

" In the present study, we have confirmed for the first time the important role of DLGAP5 in human oocyte meiotic progression. The nonsense mutation in DLGAP5 resulted in abnormal oocyte maturation and embryo development. Our study expanded the current spectrum of pathogenic genes responsible for the phenotype of oocyte maturation and embryo development defects. This study provided a theoretical basis and application values for clinical counseling, genetic diagnosis, and treatment strategies in infertile patients." Jin says.

See the article: 

DLGAP5 mutations disrupt normal chromosome segregation and spindle formation of human oocyte meiosis and lead to female infertility 

https://doi.org/10.1002/mco2.70224