A SPDYA Mutation Causes Meiotic Arrest in Non-Obstructive Azoospermia

Maturation arrest (MA) is a typical pathologic phenotype in men with Non-obstructive azoospermia (NOA), one of the most severe forms of male infertility. However, relationships between MA and meiosis-associated monogenic alterations remain largely unclear. In this study, we identified a homozygous variant (p.R199H）in SPDYA gene through whole exome sequencing in a NOA patient from a Chinese consanguineous family. SPDYA interacts with CDK2 and SUN1, potentially forming a SUN1 SPDYA CDK2 complex that is essential for the attachment of telomeres to the nuclear envelope. Bioinformatics and co-IP analyses indicated a weakened interaction between the mutant SPDYA and CDK2. Histological and immunostaining analysis indicated that spermatocytes with this mutation were incapable of repairing DNA double-strand breaks, resulting in meiotic arrest at zygotene stage of prophase I. The functional impairment of SPDYA led to significant reductions in SUN1 and CDK2 levels, widespread alterations in gene expression, and disruption of multiple signaling pathways critical for spermatogenesis. Overall, our results identify a potential genetic driver of NOA pathogenesis and highlight the role of the SPDYA protein as a regulator of prophase I progression during human meiosis, offering a potential diagnostic marker for male infertility.