Identifying a CATSPERB Variant in Unexplained Male Infertility Through Familial Exome Sequencing

Abstract

Introduction: Unexplained male infertility (UMI) refers to a situation where no underlying cause of male infertility is defined during investigations of the couple. Methods: Whole exome sequencing (WES) was performed to identify variants associated with UMI in a consanguineous Iranian family. Results: WES revealed a rare homozygous missense variant (chr14:g.92088086C>T; NM_024764.4:c.2126G>A; p.Arg709Gln) located in the extracellular region of CATSPERB in three affected siblings. This mutation resulted in the substitution of arginine 709 (R) with glutamine (Q) and co-segregated with the phenotype in other available family members. The kinematic parameters of sperm motility indicated abnormal hyperactivated movement. In-silico protein stability analysis suggests that the Arg709Gln (R709Q) alteration reduces the stability of the CATSPERB protein, potentially compromising causing defects in the overall stability of the CatSper complex. Conclusions: Our findings provide initial evidence supporting the involvement of CATSPERB variants in UMI. This is the first reported genetic variant within the CATSPERB gene associated with UMI.

Keywords: unexplained male infertility, CATSPERB, missense variation, R709Q alteration, hyper activation, familial exome sequencing