Adad2, Adenosine deaminase domain containing 2, is a testis-specific protein consisting of a double-stranded RNA binding domain and a non-catalytic adenosine deaminase domain. It is crucial for male reproduction, functioning in spermiogenesis and piRNA biogenesis [2]. It is also involved in maintaining heterochromatin in meiotic and post-meiotic male germ cells [3]. Genetic models, especially KO mouse models, have been instrumental in studying its functions.

In Adad2 knockout mouse models, male mice exhibit male-specific sterility due to abnormal spermiogenesis [2]. Deletion of Adad2 causes mislocalization of RNF17, derepression of Ping-pong activity in pachytene piRNA biogenesis, overproduction of secondary piRNAs, and disruption of P-body integrity at the meiotic stage, leading to spermatogenesis arrest at the round spermatid stage [1]. Moreover, Adad2 mutants show normal establishment but failed maintenance of the XY-body, along with abnormal autosomal heterochromatin and ultimately post-meiotic germ cell death, as it is required for Mdc1 translation [3]. Biallelic mutations in Adad2 in humans also cause spermiogenic failure and non-obstructive azoospermia, similar to the phenotype in Adad2 mutant mice [4].

In conclusion, Adad2 is essential for male fertility, with its functions in spermiogenesis, piRNA biogenesis, and heterochromatin maintenance being revealed through mouse model-based research. These findings contribute to understanding male infertility caused by Adad2-related defects, providing insights for genetic counseling and potential treatment strategies for non-obstructive azoospermia.