Novel mutations in NLRP2 and NLRP7 cause early embryonic arrest and female infertility.

PURPOSE: Early embryonic arrest is one of the reasons for the recurrent IVF/ICSI failures. We aimed to identify pathogenic mutations in female infertility patients with early embryonic arrest.

METHODS

Whole-exome sequencing was performed in the affected patients. Sanger sequencing was used on patients and their families to confirm the identified mutations. Wild-type and mutant plasmids were constructed and transfected into HeLa cells to investigate the functional effect of the identified mutations.

RESULTS

We identified three novel homozygous mutations of NLRP2 (p.Arg81*, p.Lys312del, and p.Val316Ala) and compound heterozygous mutations with a novel frameshift mutation and a novel missense mutation of NLRP7 (p.Gln315Arg fs*5 and p.Ile830Thr) in the affected individuals with early embryonic arrest. Western blot in HeLa cells showed the mutations caused a significant decrease in NLRP2 and NLRP7 to a varying degree, which impaired the stability of the proteins. Immunofluorescent staining showed some mutations altered the localization of NLRP2 and NLRP7.

CONCLUSION

This study identified novel mutations in NLRP2 and NLRP7, expanding the mutational and phenotypic spectrum of NLRP2 and NLRP7. Our findings also establish the foundation for genetic diagnosis in recurrent IVF/ICSI failure patients with early embryonic arrest.