Abstract
BackgroundAbout 10% of cases of male infertility are due to the presence of microdeletions within the long arm of the Y chromosome (Yq). Despite the large literature covering this critical issue, very little is known about the pathogenic mechanism leading to spermatogenesis disruption in patients carrying these microdeletions. In order to identify the presence of specific molecular pathways leading to spermatogenic damage, testicular gene expression profiling was carried out by employing a microarray assay in 16 patients carrying an AZFc microdeletion or affected by idiopathic infertility. Hierarchical clustering was performed pooling the data set from 26 experiments (16 patients, 10 replicates).ResultsAn intriguing and unexpected finding is that all the samples showing the AZFc deletion cluster together irrespectively of their testicular phenotypes. This cluster, including also four patients affected by idiopathic infertility, showed a downregulation of several genes related to spermatogenesis that are mainly involved in testicular mRNA storage. Interestingly, the four idiopathic patients present in the cluster showed no testicular expression of DAZ despite the absence of AZFc deletion in the peripheral blood.ConclusionsOur expression profiles analysis indicates that several forms of infertility can be triggered by a common pathogenic mechanism that is likely related to alterations in testicular mRNA storage. Our data suggest that a lack of testicular DAZ gene expression may be the trigger of such mechanism. Furthermore, the presence of AZFc deletions in mosaic or the loss of function of AZFc genes in absence of Yq deletion can perhaps explain these findings. Finally, based on our data, it is intriguing to hypothesize that DAZ gene dysfunctions can account for a larger number of previously thought "idiopathic" infertility cases and investigation of such testicular gene dysfunction can be important to reveal the molecular determinant of infertility than are undetected when only testing Yq deletions in peripheral blood.
Highlights
About 10% of cases of male infertility are due to the presence of microdeletions within the long arm of the Y chromosome (Yq)
In order to verify if the presence of an intact AZFc region in peripheral blood correlates with a normal testicular Deleted in Azoospermia (DAZ) expression, we focused our attention to the presence/absence of the specific signals for this gene on the array in all cases contained in the cluster
We hypothesize that a crucial link that can explain this phenomenon is the lack of expression of the DAZ gene in the testes these cases
Summary
About 10% of cases of male infertility are due to the presence of microdeletions within the long arm of the Y chromosome (Yq). In order to identify the presence of specific molecular pathways leading to spermatogenic damage, testicular gene expression profiling was carried out by employing a microarray assay in 16 patients carrying an AZFc microdeletion or affected by idiopathic infertility. Microdeletions of the Y chromosome long arm (Yq) represent the main molecular determinants of male infertility and account for about 10% of cases of non obstructive azoospermia or severe hypospermatogenesis [1,2,3,4,5]. Despite the large number of studies investigating the prevalence and the molecular basis of these rearrangements, the testicular gene expression of patients carrying Yq deletions is still largely unknown and so are the molecular mechanisms leading to spermatogenesis disruption. We analyzed testis expression profiles of 16 infertile patients with different testicular phenotypes, including men carrying AZFc deletions as well as subjects with idiopathic infertility
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