Male infertility has become a worldwide health problem, but the etiologies of most cases are still unknown. SEPT12, a GTP-binding protein, is involved in male fertility. Two SEPT12 mutations (SEPT12T89M and SEPT12D197N) have been identified in infertile men who had a defective sperm annulus with a bent tail. The function of SEPT12 in the sperm annulus is still unclear. Here, we found that SEPT12 formed a filamentous structure with SEPT7, 6, 2 and 4 at the sperm annulus. The SEPT12-based septin core complex was assembled as SEPT12-7-6-2-2-6-7-12 or SEPT12-7-6-4-4-6-7-12 octameric filaments. In addition, the GTP-binding domain of SEPT12 was critical for its interaction with SEPT7, and the NC-terminus of SEPT12 was required for the interaction of SEPT12 with itself to polymerize octamers into filaments. Mutant mice carrying the SEPT12D197N mutation, which disrupts SEPT12 filament formation, showed a disorganized sperm annulus, bent tail, reduced motility and loss of the SEPT ring structure at the sperm annulus. These phenotypes were also observed in an infertile man carrying SEPT12D197N. Taken together, our results demonstrate the molecular architecture of septin12 filaments at the sperm annulus, their mechanical support of sperm motility, and their correlation with male infertility.

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