A dominant-negative mutation of HSF2 associated with idiopathic azoospermia

Idiopathic azoospermia (IA) is a severe form of male infertility due to unknown causes. The HSF2 gene, encoding the heat shock transcription factor 2, had been suggested to play a significant role in the spermatogenesis process since the Hsf2-knockout male mice showed spermatogenesis defects. To examine whether HSF2 is involved in the pathogenesis of IA in human, we sequenced all the exons of HSF2 in 766 patients diagnosed with IA and 521 proven fertile men. A number of coding mutations private to the patient group, which include three synonymous mutations and five missense mutations, were identified. Of the missense mutations, our functional assay demonstrated that one heterozygous mutation, R502H, caused a complete loss of HSF2 function and that the mutant suppressed the normal function of the wild-type (WT) allele through a dominant-negative effect, thus leading to the dominant penetrance of the mutant allele. These results support a role for HSF2 in the pathogenesis of IA and further implicate this transcription factor as a potential therapeutic target.