Cylicin-1
cytoskeletal calyx
Disruption in <i>CYLC1</i> leads to acrosome detachment, sperm head deformity, and male in/subfertility in humans and mice.
The perinuclear theca (PT) is a dense cytoplasmic web encapsulating the sperm nucleus. The physiological roles of PT in sperm biology and the clinical relevance of variants of PT proteins to male infertility are still largely unknown. We reveal that cylicin-1, a major constituent of the PT, is vital for male fertility in both mice and humans. Loss of cylicin-1 in mice leads to a high incidence of malformed sperm heads with acrosome detachment from the nucleus. Cylicin-1 interacts with itself, several other PT proteins, the inner acrosomal membrane (IAM) protein SPACA1, and the nuclear envelope (NE) protein FAM209 to form an 'IAM-cylicins-NE' sandwich structure, anchoring the acrosome to the nucleus. WES (whole exome sequencing) of more than 500 Chinese infertile men with sperm head deformities was performed and a <i>CYLC1</i> variant was identified in 19 patients. <i>Cylc1</i>-mutant mice carrying this variant also exhibited sperm acrosome/head deformities and reduced fertility, indicating that this <i>CYLC1</i> variant most likely affects human male reproduction. Furthermore, the outcomes of assisted reproduction were reported for patients harbouring the <i>CYLC1</i> variant. Our findings demonstrate a critical role of cylicin-1 in the sperm acrosome-nucleus connection and suggest <i>CYLC1</i> variants as potential risk factors for human male fertility.