Loss‐of‐Function SSFA2 Variants Disrupt Fertility Through Impaired Acrosome Formation and Sperm Function

Male infertility affects millions of couples globally, yet its genetic causes often remain unknown. This study investigates the role of loss-of-function variants in SSFA2 in disrupting male fertility. Through clinical analysis of infertile men carrying compound heterozygous SSFA2 mutations and functional studies in germ cell-specific knockout mouse models, we demonstrate that SSFA2 deficiency impairs acrosome formation, sperm head morphology, and calcium signaling. Mutant sperm exhibit disrupted mitochondrial distribution, reduced CatSper channel function, and fail to trigger physiological calcium oscillations in oocytes, leading to fertilization failure. While intracytoplasmic sperm injection (ICSI) can partially rescue fertilization, early embryonic development remains compromised. Our findings establish SSFA2 as a critical regulator of acrosomal biogenesis and sperm function, providing new insights into the genetic basis of male infertility and informing clinical strategies for affected patients.