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Deregulation of sertoli and leydig cells function in patients with klinefelter syndrome as evidenced by testis transcriptome analysis.

D'Aurora M, Ferlin A, Di Nicola M, Garolla A, De Toni L, Franchi S, Palka G, Foresta C, Stuppia L, Gatta V - BMC Genomics (2015)

Bottom Line: The analysis found that, compared to controls, KS patients showed the differential up- and down-expression of 656 and 247 transcripts.Functional analysis of the deregulated transcripts indicated changes of genes involved in cell death, inflammatory response, lipid metabolism, steroidogenesis, blood-testis-barrier formation and maintenance, as well as spermatogenesis failure.The increased LCs steroidogenic function together with the impairment of inflammatory pathways and BTB structure, result in increased apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychological, Humanities and Territorial Sciences, School of Medicine and Health Sciences, "G.d'Annunzio" University, Via Dei Vestini 31, 66100, Chieti-Pescara, Italy. m.daurora@unich.it.

ABSTRACT

Background: Klinefelter Syndrome (KS) is the most common abnormality of sex chromosomes (47,XXY) and represents the first genetic cause of male infertility. Mechanisms leading to KS testis degeneration are still not completely defined but considered to be mainly the result of germ cells loss. In order to unravel the molecular basis of global testis dysfunction in KS patients, we performed a transcriptome analysis on testis biopsies obtained from 6 azoospermic non-mosaic KS patients and 3 control subjects.

Results: The analysis found that, compared to controls, KS patients showed the differential up- and down-expression of 656 and 247 transcripts. The large majority of the deregulated transcripts were expressed by Sertoli cells (SCs) and Leydig cells (LCs). Functional analysis of the deregulated transcripts indicated changes of genes involved in cell death, inflammatory response, lipid metabolism, steroidogenesis, blood-testis-barrier formation and maintenance, as well as spermatogenesis failure.

Conclusions: Taken together, present data highlight the modulation of hundreds of genes in the somatic components of KS patient testis. The increased LCs steroidogenic function together with the impairment of inflammatory pathways and BTB structure, result in increased apoptosis. These findings may represent a critical roadmap for therapeutic intervention and prevention of KS-related testis failure.

No MeSH data available.


Related in: MedlinePlus

IPA-inferred Sertoli cell–Sertoli cell junction signalling pathway. The figure shows the significant deregulation of the Sertoli cell pathway generated by the analysis of both up- and down-regulated transcript datasets, mainly involved in Blood-Testis-Barrier maintenance. In grey are labelled the genes deregulated in KS testis vs. control testis.
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Fig4: IPA-inferred Sertoli cell–Sertoli cell junction signalling pathway. The figure shows the significant deregulation of the Sertoli cell pathway generated by the analysis of both up- and down-regulated transcript datasets, mainly involved in Blood-Testis-Barrier maintenance. In grey are labelled the genes deregulated in KS testis vs. control testis.

Mentions: Expression profiling analysis revealed the significant differential expression of 903 transcripts (Additional file 2: Table S1) in KS as compared to control testis. Two clusters of differentially expressed genes (Clusters A and B) were evidenced, composed by 247 down- and 656 over-regulated transcripts in KS testis (Figure 1, Additional file 3: Table S2 and Additional file 4: Table S3). IPA analysis revealed that the 247 down-expressed genes were mainly involved in the following biological functions: DNA replication, recombination and repair, cell morphology, organ morphology, reproductive system development and function, molecular transport, cellular function and maintenance, and cell cycle (Figure 2A, Additional file 4: Table S3). Among the down-expressed genes we found only 24 transcripts specifically expressed by the germinal epithelium, being the majority of under-regulated genes expressed by SCs and LCs. On the other hand, the 656 over-expressed genes resulted involved in the following biological functions: cell death and survival, lipid metabolism, small molecule biochemistry, cellular development, cellular growth and proliferation, cell morphology, developmental disorder, reproductive system disease, free radical scavenging and molecular transport (Figure 2B, Additional file 5: Table S4). Among these transcripts, we found only 1 up-regulated X-linked gene, namely SLC25A6, located in the PAR1, and 25 under-regulated genes specifically expressed in germ cells. IPA-inferred network analysis on the data set showed for cluster A 13 networks with a score ranging from 48 down to 15, and, for cluster B, 25 networks with a score ranging from 46 down to 15. The 2 top networks associated to each cluster are reported in Figure 3. IPA pathway analysis of the two clusters showed a significant deregulation of the Sertoli cell - Sertoli cell junction signalling pathway (Figure 4). When specifically focusing on the global function played by both down- and up-regulated genes, the following classes were evidenced:


Deregulation of sertoli and leydig cells function in patients with klinefelter syndrome as evidenced by testis transcriptome analysis.

D'Aurora M, Ferlin A, Di Nicola M, Garolla A, De Toni L, Franchi S, Palka G, Foresta C, Stuppia L, Gatta V - BMC Genomics (2015)

IPA-inferred Sertoli cell–Sertoli cell junction signalling pathway. The figure shows the significant deregulation of the Sertoli cell pathway generated by the analysis of both up- and down-regulated transcript datasets, mainly involved in Blood-Testis-Barrier maintenance. In grey are labelled the genes deregulated in KS testis vs. control testis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4362638&req=5

Fig4: IPA-inferred Sertoli cell–Sertoli cell junction signalling pathway. The figure shows the significant deregulation of the Sertoli cell pathway generated by the analysis of both up- and down-regulated transcript datasets, mainly involved in Blood-Testis-Barrier maintenance. In grey are labelled the genes deregulated in KS testis vs. control testis.
Mentions: Expression profiling analysis revealed the significant differential expression of 903 transcripts (Additional file 2: Table S1) in KS as compared to control testis. Two clusters of differentially expressed genes (Clusters A and B) were evidenced, composed by 247 down- and 656 over-regulated transcripts in KS testis (Figure 1, Additional file 3: Table S2 and Additional file 4: Table S3). IPA analysis revealed that the 247 down-expressed genes were mainly involved in the following biological functions: DNA replication, recombination and repair, cell morphology, organ morphology, reproductive system development and function, molecular transport, cellular function and maintenance, and cell cycle (Figure 2A, Additional file 4: Table S3). Among the down-expressed genes we found only 24 transcripts specifically expressed by the germinal epithelium, being the majority of under-regulated genes expressed by SCs and LCs. On the other hand, the 656 over-expressed genes resulted involved in the following biological functions: cell death and survival, lipid metabolism, small molecule biochemistry, cellular development, cellular growth and proliferation, cell morphology, developmental disorder, reproductive system disease, free radical scavenging and molecular transport (Figure 2B, Additional file 5: Table S4). Among these transcripts, we found only 1 up-regulated X-linked gene, namely SLC25A6, located in the PAR1, and 25 under-regulated genes specifically expressed in germ cells. IPA-inferred network analysis on the data set showed for cluster A 13 networks with a score ranging from 48 down to 15, and, for cluster B, 25 networks with a score ranging from 46 down to 15. The 2 top networks associated to each cluster are reported in Figure 3. IPA pathway analysis of the two clusters showed a significant deregulation of the Sertoli cell - Sertoli cell junction signalling pathway (Figure 4). When specifically focusing on the global function played by both down- and up-regulated genes, the following classes were evidenced:

Bottom Line: The analysis found that, compared to controls, KS patients showed the differential up- and down-expression of 656 and 247 transcripts.Functional analysis of the deregulated transcripts indicated changes of genes involved in cell death, inflammatory response, lipid metabolism, steroidogenesis, blood-testis-barrier formation and maintenance, as well as spermatogenesis failure.The increased LCs steroidogenic function together with the impairment of inflammatory pathways and BTB structure, result in increased apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychological, Humanities and Territorial Sciences, School of Medicine and Health Sciences, "G.d'Annunzio" University, Via Dei Vestini 31, 66100, Chieti-Pescara, Italy. m.daurora@unich.it.

ABSTRACT

Background: Klinefelter Syndrome (KS) is the most common abnormality of sex chromosomes (47,XXY) and represents the first genetic cause of male infertility. Mechanisms leading to KS testis degeneration are still not completely defined but considered to be mainly the result of germ cells loss. In order to unravel the molecular basis of global testis dysfunction in KS patients, we performed a transcriptome analysis on testis biopsies obtained from 6 azoospermic non-mosaic KS patients and 3 control subjects.

Results: The analysis found that, compared to controls, KS patients showed the differential up- and down-expression of 656 and 247 transcripts. The large majority of the deregulated transcripts were expressed by Sertoli cells (SCs) and Leydig cells (LCs). Functional analysis of the deregulated transcripts indicated changes of genes involved in cell death, inflammatory response, lipid metabolism, steroidogenesis, blood-testis-barrier formation and maintenance, as well as spermatogenesis failure.

Conclusions: Taken together, present data highlight the modulation of hundreds of genes in the somatic components of KS patient testis. The increased LCs steroidogenic function together with the impairment of inflammatory pathways and BTB structure, result in increased apoptosis. These findings may represent a critical roadmap for therapeutic intervention and prevention of KS-related testis failure.

No MeSH data available.


Related in: MedlinePlus