Loss of the gene has been associated with low semen volume and sperm count, but in this case, the man had sperm characteristics that were within the normal range, Alice Luddi, Ph.D., of the University of Siena, and colleagues reported in the Feb. 26 issue of the New England Journal of Medicine.
"The association of this large deletion with normal fertility shows that USP9Y, hitherto considered a candidate gene for infertility and azoospermia, does not have a key role in male reproduction," the researchers said.
"These results suggest that it may not be necessary to consider USP9Y when screening the Y chromosome of infertile or subfertile men for microdeletions," as recommended by guidelines from the European Academy of Andrology and the European Molecular Genetics Quality Network, the researchers said.
USP9Y is found on the azoospermia factor region AZFa on the Y chromosome along with one other gene, DDX3Y. The exact roles of these genes are unclear, the researchers said, but deletions affecting this region have been associated with azoospermia or severe oligospermia.
The man identified in the current study, who had a deletion resulting in a missing USP9Y, was 42 years old and came in for an infertility evaluation after his partner had miscarried.
He underwent three spermiograms and had blood drawn to screen for deletions and to evaluate the expression of DDX3Y.
There was a slight reduction in sperm motility, the researchers said, but other sperm characteristics were in the normal range.
The patient had a normal sperm count of about 54 to 66 million per milliliter and a normal sperm phenotype. Electron microscopy revealed that a small percentage of sperm had broken plasma membranes, reacted or missing acrosomes, and disrupted chromatin.
The patient's karyotype was normal, and the frequency of chromosome 18 disomy and the rate of diploidy were similar to those among fertile men.
The man, his father, and his brother all shared a deletion in the AZFa region that affected USP9Y but not DDX3Y.
"Since deletions in USP9Y have been reported to cause mild-to-severe oligospermia or azoospermia, a phenotype not observed in our patient, we considered mosaicism as an explanation for the fertility of this subject," the researchers said.
However, DNA from all spermatozoa contained the same deletion.
Previously described fertility problems, therefore, "cannot be due to deletion of USP9Y alone," the researchers said. "Additional genetic or nongenetic factors must influence the phenotype."
Variables that might come into play are local testicular factors or the environmental or genetic background of the patient, they said.
Because of the difficulty in nailing down the genes relevant to spermatogenesis and male fertility, the study findings represent "a noteworthy advance in the field," according to Chris Tyler-Smith, Ph.D., of the Wellcome Trust Sanger Institute in Hinxton, England, and Csilla Krausz, M.D., Ph.D., of the University of Florence in Italy.
In an accompanying editorial, they said that the seemingly simple task of determining whether USP9Y or DDX3Y are responsible for the azoospermic phenotype associated with deletions in this region is complicated by the rarity of such mutations.
In addition, they said, deletions that result in azoospermia obviously cannot be inherited and all confirmed mutations affecting a single gene have involved USP9Y. So there is no information on what happens when DDX3Y alone is lost.
Sertoli-cell-only syndrome, which is consistently characterized by a lack of germ cells, results when both genes are deleted, which demonstrates that DDX3Y is important in spermatogenesis, the editorialists said.
The study findings indicate that "screening for USP9Y deletion should not be performed routinely until there is a better understanding of the factors that modify the phenotype," and focus attention on the need for a better understanding of the role of DDX3Y, they said.
| The study was supported in part by a grant from Monte dei Paschi di Siena Bank.
Zalman S. Agus, MD Emeritus Professor
University of Pennsylvania School of Medicine
New England Journal of MedicineSource Reference: Luddi A, et al "Spermatogenesis in a man with complete deletion of USP9Y" N Engl J Med 2009; 360: 881-885.
New England Journal of MedicineSource Reference: Tyler-Smith C, Krausz C "The will-o'-the wisp of genetics -- hunting for the azoospermia factor gene" N Engl J Med 2009; 360: 925-927.