Abstract
The main genetic cause of male infertility is represented by the Klinefelter Syndrome (KS), a condition accounting for 3% of all cases of infertility and up to15% of cases of azoospermia. KS is generally characterized by azoospermia; approximately 10% of cases have severe oligozoospermia. Among these, the 30–40% of patients show hypospermatogenesis. The mechanisms leading to adult testis dysfunctions are not completely understood. A microarray transcriptome analysis was performed on testis biopsies obtained from three KS patients with hypospermatogenesis and three control subjects. KS testis showed a differential up- and down-regulation of 303 and 747 transcripts, respectively, as compared to controls. The majority of down-regulated transcripts were involved in spermiogenesis failure and testis morphological defects, whereas up-regulated genes were responsible for testis apoptotic processes. Functional analysis of the transcriptionally altered genes indicated a deregulation in cell death, germ cell function and morphology as well as blood-testis-barrier maintenance and Leydig cells activity. These data support a complex scenario in which spermatogenic impairment is the result of functional and morphological alterations in both germinal and somatic components of KS testis. These findings could represent the basis for evaluating new markers of KS spermatogenesis and potential targets of therapeutic intervention to preserve residual spermatogenesis.
Highlights
The Klinefelter Syndrome (KS) is the most common aberration of sex chromosomes, with a prevalence of 1:600–1:1000 in newborn males, it is generally diagnosed in the adulthood[1]
Functional Ingenuity Pathway Analysis (IPA) of the two gene clusters revealed that the 747 down-regulated genes were mainly involved in the following biological functions: organismal injury and abnormalities, reproductive system disease, cell and organ morphology, reproductive system development and function, cellular movement, inflammatory response and endocrine system disorders (Fig. 2A)
CREM is the key node of IPA-inferred second network (Fig. 4A), which negatively regulates the expression of other essential spermatogenesis factors such as FHL5 and PRM1 and PRM2
Summary
The Klinefelter Syndrome (KS) is the most common aberration of sex chromosomes, with a prevalence of 1:600–1:1000 in newborn males, it is generally diagnosed in the adulthood[1]. KS represents the main genetic cause of male infertility being present in 3% of infertile men and 15% of azoospermic men[2]. KS patients are traditionally described as azoospermic in approximately 90% of cases, evidencing primary testicular failure, small firm testes and hypergonadotropic hypogonadism[4], the phenotype is often highly variable. The molecular mechanisms underlying the dysfunction in KS testis have been poorly investigated and the causes of global testicular degeneration are still unclear. The presence of an additional X-chromosome seems to significantly impair spermatogenesis at an early stage[10,11]. The molecular networks involved in KS spermatogenic and testicular failure could represent the basis for the identification of new therapy targets and the set-up of early treatments preserving residual fertility
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