Novel mutations in the PLCZ1 gene associated with human low or failed fertilization.

Background: Fertilization failure (FF) is a complex reproductive disorder characterized by the failure of pronuclei formation during fertilization. In addition to some cases caused by iatrogenic problems and known genetic factors, there are still many unexplained aspects of FF. Here, we aimed to assess the clinical and genetic characteristics of two families experiencing primary infertility with FF.

Methods: We have characterized two families from China. All of the infertile couples presented with similar clinical phenotypes, that is, partial or total fertilization failure in repeated cycles. We performed Sanger sequencing of their WEE2, TLE6, and PLCZ1 genes, and further bioinformatics and functional analyses were performed to identify the pathogenic elements of the variants.

Results: We identified novel compound heterozygous mutations c.1259C>T (p.P420L) and c.1733T>C (p.M578T) in the PLCZ1 gene in a male patient of family 1 with total fertilization failure, and another novel homozygous mutation c.1727T>C (p.L576P) in the same gene in a male patient of family 2 with partial fertilization failure. These three novel mutations were absent in the control cohort and in the databases. The amino acids were conserved at their positions among six different species. All mutant amino acids were located in key domains and were predicted to impair hydrolytic activity and lead to PLCZ1 dysfunction. Further functional detection revealed that the three mutations could significantly impair the catalytic activity of PLCZ1.

Conclusions: We identified three novel mutations in PLCZ1 associated with partial and total fertilization failure and have provided new evidence about the genetic basis of FF.