IQCN disruption causes fertilization failure and male infertility due to manchette assembly defect

Abstract

Abstract Total fertilization failure (TFF) is an important cause of infertility; however, the genetic basis of TFF caused by male factors remains to be clarified. In this study, whole‐exome sequencing was firstly used to screen for genetic causes of TFF after intracytoplasmic sperm injection (ICSI), and homozygous variants in the novel gene IQ motif‐containing N (IQCN) were identified in two affected individuals with abnormal acrosome structures. Then, Iqcn‐knockout mice were generated by CRISPR‐Cas9 technology and showed that the knockout male mice resembled the human phenotypes. Additionally, we found that IQCN regulates microtubule nucleation during manchette assembly via calmodulin and related calmodulin‐binding proteins, which resulted in head deformity with aberrant oocyte activation factor PLCζ. Fortunately, ICSI with assisted oocyte activation can overcome IQCN‐associate TFF and male infertility. Thus, our study firstly identified the function of IQCN, highlights the relationship between the manchette assembly and fertilization, and provides a genetic marker and a therapeutic option for male‐source TFF.

Keywords

• calmodulin
• fertilization failure
• IQCN
• manchette
• PLCζ