Mutations of SOX30 are identified in azoospermic human patients and reduce sperm in mice

Sox proteins constitute a family of transcription factors now thought to play essential roles in cell fate decisions and tissue regeneration. SOX30 is a testis-specific transcription regulator for activating the postmeiotic haploid gene program, and knockout of Sox30 results in defects in meiotic exit with an arrest at the early stage of round spermatids. Here, we aim to investigate the impact of human SOX30 mutagenesis on this transcriptional regulatory axis and its contribution to male infertility. Genetic screen of a cohort of 620 patients with non-obstructive azoospermia identified six heterozygous sequence variations in SOX30. Its coding region contains five missense mutations and one stop-gained mutation (Arg478*), which is predicted to lead to the production of a C-terminal truncated protein. In vitro functional evaluation shows that this C-terminal truncated SOX30 protein exhibits a dramatic loss of its protein association with the histone deacetylase HDAC3, and the missense mutation in the HMG domain reduces its DNA-binding ability. We chose to model the human P353S mutation, by generating Sox30P382S knock-in mice with a point mutation in the HMG domain of the mouse Sox30 gene. Sox30P382S mutants are fertile, but this P382S point mutation causes defects in the late stages of spermatocytes that reduce mature sperm. These results suggest SOX30 mutations may contribute to the risk of non-obstructive azoospermia in humans.