| Description |
Antizyme 3 (AZ3, OAZ3) is a testis-specific member of the antizyme gene family. The antizymes play an important role in the regulation of polyamine levels. Polyamines are small, ubiquitous, positively charged molecules important for cell growth and differentiation. Members of the antizyme family regulate polyamine levels through a unique negative feedback system. When polyamine levels rise to a critical level, they induce a +1 frameshift in the antizyme mRNA, which results in the translation of the full-length antizyme protein. The antizyme protein next binds ornithine decarboxylase, the rate-limiting enzyme in polyamine production, and inactivates it. Mutations in AZ3 are not a common cause of male infertility. A screen of 192 infertile men, 48 men of known paternity, and 34 African aborigines identified a total of 23 polymorphisms in the AZ3 gene. Haplotype analysis identified 15 different haplotypes, which separate into two divergent clusters and appear to be maintained by balancing selection. Some haplotypes in the activator of CREM in the testis gene may be associated with male subfertility. Fourteen haplotypes were identified in the gene, one of which was associated with significant decreases in the interaction between ACT and CREM. Antizyme 3 interacts with several different proteins. A screen of a human, adult-testis cDNA library identified three novel interaction partners. These include WDR46, PSPC1 and OPLAH. The interactions were confirmed using coimmunoprecipitation assays and beta-galactosidase assays. In addition, interactions were also identified between AZ3 and the ODC-like protein. Analysis of cell-specific cDNA indicates expression of these proteins overlaps with AZ3 expression in the testis. Expression of antizyme 1 and 2 was also identified in haploid germ cells, suggesting AZ3 might have a role in spermatogenesis beyond regulation of polyamine levels. Ongoing research on AZ3 includes the development of an RNAi knockdown model. To date, shRNA constructs have been designed that silence AZ3 in vitro. Ultrasound-assisted DNA delivery is currently being tested to deliver the shRNA genes to the testis in mice. |
