![]() Nephrocystin is involved in spermatogenesis and is required for the differentiation of early elongating spermatids into spermatozoa. bcar1 interacts with nephrocystin and both proteins localize to cell-cell contacts of polarized epithelial cells. crebbp is responsible for handling Gap 1 (G1) arrest during the cell cycle and bcar1 is responsible for the maintenance of the cell in the focal adhesion pathway. The Key Nodes of the PPI NetworkĮxamination of the key nodes identified in our PPI network suggested proteins crebbp and bcar1, which have never been associated with azoospermia. ![]() A histogram is used to plot the distribution of the shortest paths ( Figure 1A). The degree exponent value is lower than 3, which is similar to the other networks following a scale-free distribution and similar to values of other human protein networks. The shortest path analysis of the network showed that any two randomly selected nodes on the network were connected via 2.85 links. The mean degree value of the protein nodes is 7.05. The R package was used to calculate the topological parameters. The retrieved data were entered into Cytoscape 2.8 to construct the PPI network. Examination of the identified proteins in Protein-Protein Interaction (PPI) data from the Human Protein Reference Database (HPRD database) showed that there are 209 related proteins with 737 links (refer to the supplementary file). The initial selection of proteins from the Online Mendelian Inheritance in Man (OMIM) database produced 86 proteins associated with azoospermia (refer to supplementary file). Therefore, while understanding the overall mechanism of azoospermia is very important to improve the medical therapy, the underlying etiology and mechanism(s) remain elusive. Previous research has studied the medical treatment to improve the sperm quality of the patients before carrying out ICSI cycles. Although intracytoplasmic sperm injection (ICSI) as an assisted reproductive technology is an efficient therapy for severe male infertility, the success rate for NOA cases following ICSI therapy is around 36%. Non-obstructive azoospermia (NOA) is considered to be a severe male infertility factor due to the impaired spermatogenesis with the consequent absence of spermatozoa in the ejaculate. Despite this, azoospermia is always taken as a matter of serious interest while treating the issues related to infertility. The increasing role of the male factor in cases of couples’ infertility has been identified due to the increased evaluation of male reproductive function and the development of new diagnostic tools. Male factor infertility is involved in over 50% of couples trying to conceive. Two new genes and associated diseases are promising for further experimental validation. The KEGG analysis also showed 45 statistically important pathways with 31 proteins associated with colorectal, pancreatic, chronic myeloid leukemia and prostate cancer. The gene ontology analysis suggests a genetic link between azoospermia and liver disease. We also identified new candidate genes, CREBBP and BCAR1, which may play a role in azoospermia. ![]() Mathematical analysis identified three proteins, ar, dazap2, and esr1, as hub nodes and a bottleneck protein within the network. Using Online Mendelian Inheritance in Man, the Human Protein Reference Database and Cytoscape, we created a novel network consisting of 209 protein nodes and 737 interactions. In the presented study, in order to identify all possible candidate genes associated with azoospermia and to map their relationship, we present the first protein-protein interaction network related to azoospermia and analyze the complex effects of the related genes systematically. Currently, the etiology of this condition remains elusive with several possible molecular pathway disruptions identified in the post-meiotic spermatozoa. Non-obstructive azoospermia is a severe infertility factor.
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