A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa

Calcium signalling is critical for successful fertilization. In spermatozoa, capacitation, hyperactivation of motility and the acrosome reaction are all mediated by increases in intracellular Ca2+. Cation channels of sperm proteins (CATSPERS1-4) form an alkalinization-activated Ca2+-selective channel required for the hyperactivated motility of spermatozoa and male fertility. Each of the CatSper1-4 genes encodes a subunit of a tetramer surrounding a Ca2+-selective pore, in analogy with other six-transmembrane ion channel a subunits. In addition to the pore-forming proteins, the sperm Ca2+ channel contains auxiliary subunits, CATSPER beta and CATSPER gamma. Here, we identify the Tmem146 gene product as a novel subunit, CATSPER delta, required for CATSPER channel function. We find that mice lacking the sperm tail-specific CATSPERd are infertile and their spermatozoa lack both Ca2+ current and hyperactivated motility. We show that CATSPERd is an essential element of the CATSPER channel complex and propose that CATSPERd is required for proper CATSPER channel assembly and/or transport.