Natural transmission of USP9Y gene mutations: a new perspective on the role of AZFa genes in male fertility

Abstract

Deletions of the azoospermia factor (AZF) regions of the Y chromosome are associated with severe spermatogenic failure and represent the most frequent molecular genetic cause of azoospermia and severe oligozoospermia. The exact role of the candidate AZF genes is largely unknown due to both the extreme rarity of naturally occurring AZF gene-specific mutations and the lack of functional assays. Here, we report the fine characterization of two different deletions in the USP9Y gene (one of the two candidate genes in the AZFa region), which have been transmitted through natural conception in two unrelated families. The associated mild testicular phenotype, in both cases, is in sharp contrast with that of the two previously reported infertile patients bearing a mutation of the same gene. In conclusion, to date, the USP9Y gene has been considered as one of the major Y-linked spermatogenesis genes, based on both its position within the AZFa region and previous reports that correlated USP9Y mutation to severe spermatogenic failure and infertility. This view is now substantially changed because our findings clearly demonstrate that during human spermatogenesis, USP9Y is more likely a fine tuner that improves efficiency, rather than a provider of an essential function. More importantly, the observed natural conceptions suggest that the protein is not required for the final sperm maturation process or for the acquisition of sperm fertilizing ability, providing a new perspective on the role played by the USP9Y gene in male fertility.

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

“…On the contrary, patients with deletions of both USP9Y and DBY seem to invariably demonstrate azoospermia with a testicular histology of SCOS [17,49]. Deletion of the USP9Y gene can additionally cause azoospermia, oligozoospermia, or oligoasthenozoospermia [15,50].…”

“…2) [57]. Deletions of the AZFc locus occur more frequently (65-70 %) than AZFa or AZFb locus [15]. Deletions of the AZFc locus manifest in 10-20 % of infertile men [58] and specifically in cases of moderate oligozoospermia (0.7 %), severe oligozoospermia (4-14 %), or secretory azoospermia (11-18 %) [41].…”

“…Detailed mechanistic studies of these genes have aided in the development of diagnostic tests to test male infertility and therapeutic strategies to overcome infertility, particularly in men undergoing the ICSI procedure. To name a few, testicular mapping, genetic analysis at the chromosomal level (karyotyping), androgen receptor gene mutations, CF test and Y chromosome micro deletion analysis are being used routinely in diagnosis of male factor infertility [15]. In addition, some molecular cytogenetic methods such as comet assay, sperm-chromatin-dispersion assay (SCD), transferase-mediated dUTP nicked labeling (TUNEL), or sperm chromatin structure assay (SCSA) have been developed for the detection of DNA damage [4].…”

“…Genetic abnormalities leading to male infertility are responsible for 15 to 30 % of cases, with a prevalence of Y chromosome abnormalities [14,15]. Whereas many other genetic abnormalities that cause male infertility are still unknown, it is likely that most cases of idiopathic infertility could be accounted for by underlying genetic causes [16].…”

Evaluation of the azoospermic male

“…[62][63][64] Partial deletions involving only USP9Y (and not DDX3Y; USP9Y and DDX3Y are the two testis specific genes within the AZFa region) may occur and still allow spermatogenesis to occur. 65 Briefly, for the NOA patient, if an AZFa, AZFb or AZFb/c microdeletion is discovered, there is little likelihood, if any, of spermatozoa being harvested from the testis tissue. 59,[66][67][68][69] When an AZFc microdeletion is detected in the NOA male, up to 70% will have retrievable spermatozoa from the testis tissue while 30% will have no sperm found.…”