Disease relevance of USP9Y

• This mutation was present in a man with nonobstructive azoospermia (that is, no sperm was detected in semen), but absent in his fertile brother, suggesting that the USP9Y mutation caused spermatogenic failure [1].
• Ubiquitin-specific protease activity of USP9Y, a male infertility gene on the Y chromosome [2].
• 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 [3].
• The DFFRY-derived peptide was recognized by an HLA-A1 restricted CTL clone, generated during graft rejection from a female patient with acute myeloid leukemia who rejected HLA-phenotypically identical bone marrow from her father [4].
• OBJECTIVE: To investigate lineage-specific chimerism of plasma cells after allogeneic transplantation by real-time PCR based on bi-allelic sequence polymorphism or, in case of female-to-male transplantation, on the detection of the DFFRY gene and to determine its value to quantify minimal residual disease in myeloma patients [5].

High impact information on USP9Y

• There is no Ube1y1 homolog in man, and DBY, either alone or in conjunction with USP9Y, is the favored candidate for an early spermatogenic role [6].
• An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y [1].
• 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 [3].
• However, A1-HY-specific CTL recognize the DFFRY-derived peptide at a 1500-fold lower dose than the female homologue [7].
• RESULTS: The expression of USP9Y, USP9X and DDX3Y was found in all the specimens tested, whereas DDX3Yt1 expression was diminished or undetectable in several biopsies with impaired spermatogenesis [8].

Biological context of USP9Y

• While deletions or even smaller mutations in USP9Y seem to be associated with a testicular phenotype of severe hypospermatogenesis, patients with deletions of DBY may present both Sertoli cell-only syndrome and severe hypospermatogenesis [9].
• On the contrary, the phenotype of patients with deletion of both USP9Y and DBY seem to be invariably azoospermia with a testicular histology of Sertoli cell-only [9].
• Cutting edge: the HLA-A*0101-restricted HY minor histocompatibility antigen originates from DFFRY and contains a cysteinylated cysteine residue as identified by a novel mass spectrometric technique [7].
• In all haplotype II Japanese men, we found that DFFRY gene harbors a (C-->T) substitution polymorphism that was not found in any other population of this study [10].

Anatomical context of USP9Y

• These results suggest that, through de-ubiquitination, USP9Y may stabilize a specific target protein that is important for male germ cell development [2].
• DFFRY codes for a new human male-specific minor transplantation antigen involved in bone marrow graft rejection [4].

Other interactions of USP9Y

• Both USP9Y and DBY may cause severe testiculopathies, but DBY appears to be the major AZFa candidate [11].
• All samples (n=28), including five controls, showed normal expression of actin, SRY and USP9Y [12].
• A preliminary report on the implication of RT-PCR detection of DAZ, RBMY1, USP9Y and Protamine-2 mRNA in testicular biopsy samples from azoospermic men [12].
• The region includes the genes USP9Y, DBY and UTY and is limited by evolutionary breakpoints within the PAC clones 41L06 and 46M11 [13].
• Case 1 also had deletion of the putative growth controlling gene (GCY) and the Yq breakpoint was located between sY741 and USP9Y [14].

Analytical, diagnostic and therapeutic context of USP9Y

• By using denaturing HPLC, these two genes, as well as DBY and DFFRY, were screened for polymorphic sites in 53-72 representatives of the five continents [15].
• Two markers, DFFRY and DAZ, were tested by nested polymerase chain reaction (PCR) in the two series [16].

References