Protamine 2 precursors, protamine 1/protamine 2 ratio, DNA integrity and other sperm parameters in infertile patients

Torregrosa, Nuria; Domínguez-Fandos, David; Camejo, María Isabel; Shirley, Cynthia R.; Meistrich, Marvin L.; Ballescà, Josep Lluís; Oliva, Rafael

doi:10.1093/humrep/del114

Cited by 141 publications

(121 citation statements)

References 44 publications

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“…4), implying impaired sperm quality. Protamine deficiency in mature sperm from both mice and humans has been reported as a manifestation of DNA damage and fertility problems, as the protamine structure protects the genetic material from physical and chemical damage (35,36).…”

Section: Discussionmentioning

confidence: 99%

Promoter ChIP-chip analysis in mouse testis reveals Y chromosome occupancy by HSF2

Åkerfelt

Henriksson

Laiho

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The mammalian Y chromosome is essential for spermatogenesis, which is characterized by sperm cell differentiation and chromatin condensation for acquisition of correct shape of the sperm. Deletions of the male-specific region of the mouse Y chromosome long arm (MSYq), harboring multiple copies of a few genes, lead to sperm head defects and impaired fertility. Using chromatin immunoprecipitation on promoter microarray (ChIP-chip) on mouse testis, we found a striking in vivo MSYq occupancy by heat shock factor 2 (HSF2), a transcription factor involved in spermatogenesis. HSF2 was also found to regulate the transcription of MSYq resident genes, whose transcriptional regulation has been unknown. Importantly, disruption of Hsf2 caused a similar phenotype as the 2/3 deletion of MSYq, i.e., altered expression of the multicopy genes and increased mild sperm head abnormalities. Consequently, aberrant levels of chromatin packing proteins and more frequent DNA fragmentation were detected, implying that HSF2 is required for correct chromatin organization in the sperm. Our findings define a physiological role for HSF2 in the regulation of MSYq resident genes and the quality of sperm. chromatin packing ͉ heat shock factor ͉ MSYq ͉ promoter microarray ͉ spermatogenesis

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Section: Discussionmentioning

confidence: 99%

Promoter ChIP-chip analysis in mouse testis reveals Y chromosome occupancy by HSF2

Åkerfelt

Henriksson

Laiho

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Both protamines 1 and 2 are essential for sperm function, and the haploinsufficiency of either P1 or P2 results in a reduced amount of the respective protein, abnormalities in the structure of the chromatin, DNA damage and infertility [148]. Furthermore, it is known that the optimal protamine-1 to protamine-2 ratio (P1/P2 ratio) is critical and well regulated [166]. Indeed, the P1/P2 ratio in fertile men ranges from 0.8 to 1.2 and deviation from this ratio has been shown to lead to infertility [167].…”

Section: Epigenetic Modifications and Male Infertilitymentioning

confidence: 99%

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

Tahmasbpour

Balasubramanian

Agarwal

2014

J Assist Reprod Genet

107

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Background The assisted reproductive techniques aimed to assist infertile couples have their own offspring carry significant risks of passing on molecular defects to next generations. Results Novel breakthroughs in gene and protein interactions have been achieved in the field of male infertility using genome-wide proteomics and transcriptomics technologies. Conclusion Male Infertility is a complex and multifactorial disorder.Significance This review provides a comprehensive, up-todate evaluation of the multifactorial factors involved in male infertility. These factors need to be first assessed and understood before we can successfully treat male infertility.

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“…These findings suggest that genetic sequence aberrations are an unlikely cause for protamine deficiency. Subsequent studies reported that patients with an elevated P1=P2 ratio under-expressed P2 protein and retained higher levels of protamine 2 transcript when compared to patients with normal or high P2 protein [Aoki et al 2006c;Torregrosa et al 2006]. However, patients with a diminished P1=P2 ratio under-expressed P1 protein and over-expressed P1 transcript [Aoki et al 2006c;Torregrosa et al 2006].…”

Section: Introductionmentioning

confidence: 99%

“…Subsequent studies reported that patients with an elevated P1=P2 ratio under-expressed P2 protein and retained higher levels of protamine 2 transcript when compared to patients with normal or high P2 protein [Aoki et al 2006c;Torregrosa et al 2006]. However, patients with a diminished P1=P2 ratio under-expressed P1 protein and over-expressed P1 transcript [Aoki et al 2006c;Torregrosa et al 2006]. Previous studies have indicated that patients with an elevated protamine 2 transcript had higher levels of DNA damage [Torregrosa et al 2006], whereas patients with increased protamine 1 transcript retention had low sperm motility [Lambard et al 2004;Aoki et al 2006c].…”

Section: Introductionmentioning

confidence: 99%

“…However, patients with a diminished P1=P2 ratio under-expressed P1 protein and over-expressed P1 transcript [Aoki et al 2006c;Torregrosa et al 2006]. Previous studies have indicated that patients with an elevated protamine 2 transcript had higher levels of DNA damage [Torregrosa et al 2006], whereas patients with increased protamine 1 transcript retention had low sperm motility [Lambard et al 2004;Aoki et al 2006c]. This variation in transcript retention may be explained by reduced protamine transcription, altered translation of the transcript or simply altered retention of unprocessed transcripts, but this is inconclusive as to the cause of altered transcript retention.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Genetic Variation in the 5′ and 3′ Non-coding Regions of the Protamine Genes in Patients with Protamine Deregulation

Hammoud

Emery

Aoki

et al. 2007

Archives of Andrology

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Deregulation of sperm nuclear protamine ratio (P1=P2) has been shown to correlate with male factor infertility in humans, but the cause of this abnormal protein expression has yet to be identified. Recent studies have shown that there is little genetic variability in the coding regions of either of the protamine gene sequences. However, these studies did not investigate the 5 0 or 3 0 non-coding regions of these genes for mutations that might account for changes in the transcriptional or translational regulation of the protamines.In an effort to determine if genetic variation in these non-coding regions may account for aberrant protamine expression, we have sequenced the 5 0 and 3 0 untranslated regions (UTRs) of both protamine 1 (P1) and protamine 2 (P2) genes in a population of infertile men with protamine deregulation, men presenting for infertility work-up with normal protamine ratios, and a population of unrelated, fertile men from the Utah Genetic Reference Project (UGRP). This analysis has identified 14 single nucleotide polymorphisms (SNPs), of which 13 were novel SNPs in the UTRs of P1 and P2, and verified the existence of a variable length repeat (VLR), GA n , in the P2 5 0 region. The SNP frequencies and VLR allelic frequencies did not achieve statistical significance between the populations, however, one of the SNPs identified in the 3 0 UTR of protamine 2 was found at a low frequency in the abnormal protamine patients, but was completely absent in men with verified normal protamine ratio and donors of known fertility.In conclusion, a number of SNPs have been reported in the protamine genes and the untranslated regions, however, these gene variants do not appear to be responsible for protamine deficiency. Hence, the underlying cause for aberrant protamine expression may possibly be due to abnormalities in candidate spermatogenic transcriptional=translational regulators, post-translational modifiers, or as-of-yet unidentified factors affecting the testicular environment.

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Protamine 2 precursors, protamine 1/protamine 2 ratio, DNA integrity and other sperm parameters in infertile patients

Cited by 141 publications

References 44 publications

Promoter ChIP-chip analysis in mouse testis reveals Y chromosome occupancy by HSF2

Promoter ChIP-chip analysis in mouse testis reveals Y chromosome occupancy by HSF2

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

Identification of Genetic Variation in the 5′ and 3′ Non-coding Regions of the Protamine Genes in Patients with Protamine Deregulation

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