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UBE2B mRNA alterations are associated with severe oligozoospermia in infertile men.

ABSTRACT: Oligozoospermia (low sperm count) is a common semen deficiency. However, to date, few genetic defects have been identified to cause this condition. Moreover, even fewer molecular genetic diagnostic tests are available for patients with oligozoospermia in the andrology clinic. Based on animal and gene expression studies of oligozoospermia, several molecular pathways may be disrupted in post-meiotic spermatozoa. One of the disrupted pathways is protein ubiquitination and cell apoptosis. A critical protein involved in this pathway is the ubiquitin-conjugating enzyme 2B, UBE2B. Absence of Ube2b in male mice causes spermatogenic meiotic disruption with increased apoptosis, leading to infertility. To examine the association between messenger RNA defects in UBE2B and severe oligozoospermia (0.1-10 × 10(6) cells/ml), sequencing of sperm cDNA in 326 oligozoospermic patients and 421 normozoospermic men was performed. mRNA alterations in UBE2B were identified in sperm in 4.6% (15 out of 326) of the oligozoospermic patients, but not found in control men, suggesting strong association between mRNA defects and oligozoospermia (?(2) = 19, P = 0.0001). Identified UBE2B alterations include nine splicing, four missense and two nonsense alterations. The follow-up screen of corresponding DNA regions did not reveal causative DNA mutations, suggesting a post-transcriptional nature of identified defects. None of these variants were reported in the dbSNP database, although other splicing abnormalities with low level of expression were present in 11 out of 421 (2.6%) controls. Our findings suggest that two distinct molecular mechanisms, mRNA editing and splicing processing, are disrupted in oligozoospermia. We speculate that the contribution of post-transcriptional mRNA defects to oligozoospermia could be greater than previously anticipated.

SUBMITTER: Yatsenko AN

PROVIDER: S-EPMC3655768 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe etiology of varicocele, a common cause of male factor infertility, remains unclear. Proteomic changes responsible for the underlying pathology of unilateral varicocele have not been evaluated. The objective of this prospective study was to employ proteomic techniques and bioinformatic tools to identify and analyze proteins of interest in infertile men with unilateral varicocele.MethodsSpermatozoa from infertile men with unilateral varicocele (n=5) and from fertile men (control; n=5) were pooled in two groups respectively. Proteins were extracted and separated by 1-D SDS-PAGE. Bands were digested and identified on a LTQ-Orbitrap Elite hybrid mass spectrometer system. Bioinformatic analysis identified the pathways and functions of the differentially expressed proteins (DEP).ResultsSperm concentration, motility and morphology were lower, and reactive oxygen species levels were higher in unilateral varicocele patients compared to healthy controls. The total number of proteins identified were 1055, 1010 and 1042 in the fertile group, and 795, 713 and 763 proteins in the unilateral varicocele group. Of the 369 DEP between both groups, 120 proteins were unique to the fertile group and 38 proteins were unique to the unilateral varicocele group. Compared to the control group, 114 proteins were overexpressed while 97 proteins were underexpressed in the unilateral varicocele group. We have identified 29 proteins of interest that are involved in spermatogenesis and other fundamental reproductive events such as sperm maturation, acquisition of sperm motility, hyperactivation, capacitation, acrosome reaction and fertilization. The major functional pathways of the 359 DEP related to the unilateral varicocele group involve metabolism, disease, immune system, gene expression, signal transduction and apoptosis. Functional annotations showed that unilateral varicocele mostly affected small molecule biochemistry and post-translational modification proteins. Proteins expressed uniquely in the unilateral varicocele group were cysteine-rich secretory protein 2 precursor (CRISP2) and arginase-2 (ARG2).ConclusionsThe expression of these proteins of interest are altered and possibly functionally compromised in infertile men with unilateral varicocele. If validated, these proteins may lead to potential biomarker(s) and help better understand the mechanism involved in the pathophysiology of unilateral varicocele in infertile men.

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UBE2B mRNA alterations are associated with severe oligozoospermia in infertile men.

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