Primate-specific SSX1 is required for CPSF6-dependent spermatocyte transcription and human fertility

Genetic variation is a major cause of male infertility, and defining the underlying mechanisms is essential for developing effective interventions. SSX1 is a primate specific gene whose deficiency has been linked to sperm malformations in humans and cynomolgus monkeys, yet its pathogenic mechanism remains unclear. Here, by whole exome sequencing of a cohort of 536 men with oligoasthenoteratozoospermia(OAT), we identified three previously unreported SSX1 variants, including two deletion alleles and one selective splice site variant. SSX1 deficiency was associated with a characteristic OAT phenotype featuring short, coiled flagella and severe loss of the central pair microtubules. SSX1 is expressed in early spermatocytes, and its loss disrupted the expression of spermiogenesis and sperm function related genes that are transcribed in advance during the spermatocyte stage. Mechanistically, SSX1 acts as a transcriptional regulator by interacting with the transcription and processing factor CPSF6 and promoting nuclear recruitment of the CPSF complex, with functional relevance in both spermatocytes and spermatids. Collectively, our study supports a functional role for SSX1 with CPSF6 in human spermatogenesis, expands the genetic diagnostic spectrum of OAT, and provides a transcription focused framework for precision management of male infertility.