Identification of novel polymorphisms in the nuclear protein genes and their relationship with human sperm protamine deficiency and severe male infertility

Aoki, Vincent W.; Christensen, Greg L.; Atkins, John F.; Carrell, Douglas T.

doi:10.1016/j.fertnstert.2006.04.033

Cited by 58 publications

(83 citation statements)

References 20 publications

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“…Indeed, many investigators have attempted to identify any significant mutations in the protamine coding regions [de Yebra and Oliva 1993;Schlicker et al 1994;Aoki et al 2006a]. However, Tanaka, et al in 2003 identified one azoospermic patient with a premature stop codon in P2 [Tanaka et al 2003].…”

Section: Discussionmentioning

confidence: 99%

“…Several groups evaluated the coding sequences of protamine 1, 2 and transition protein 1, 2 to identify specifically relevant alterations that may possibly explain the cause of protamine deregulation [de Yebra and Oliva 1993;Schlicker et al 1994;Tanaka et al 2003;Miyagawa et al 2005;Aoki et al 2006a;Iguchi et al 2006]. Generally, there was no correlation between the absence of protamines and mutations within the coding regions of the protamine genes or transition protein genes.…”

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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…Spermiogenesis is the final stage of spermatogenesis, during which spermatids mature into motile spermatozoa. During this process, the nucleosomal structure undergoes major changes to condense the genome [9][10][11]44]. At this stage, several testisspecific subtypes of histone are synthesized and replace their somatic counterparts during the premeiotic, meiotic, and postmeiotic stages of the differentiation of germ cells [9][10][11].…”

Section: Discussionmentioning

confidence: 99%

“…However, the detailed molecular mechanisms behind infertility remain uncertain. As reported previously, transition nuclear protein genes (TNPs) play an important role in nuclear formation during spermiogenesis [1,[7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…In mice, TNP2 mRNAs are first detected in step 7 round spermatids, and are then degraded at steps 13 and 14, respectively [12,14,15]. Furthermore, TNPs are phosphorylated by sperm-specific protein kinase A, and this phosphorylation/dephosphorylation cycle has been found to play an important role in the chromatin condensation process [9][10][11]. TNPs are removed from condensing chromatin and replaced by PRMs [13], which constitute the major nuclear proteins of condensed spermatids and mature spermatozoa [12,[14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-122 Influences the Development of Sperm Abnormalities from Human Induced Pluripotent Stem Cells by Regulating TNP2 Expression

Liu

Huang²,

Liu

et al. 2013

Stem Cells and Development

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Sperm abnormalities are one of the main factors responsible for male infertility; however, their pathogenesis remains unclear. The role of microRNAs in the development of sperm abnormalities in infertile men has not yet been investigated. Here, we used human induced pluripotent stem cells to investigate the influence of miR-122 expression on the differentiation of these cells into spermatozoa-like cells in vitro. After induction, mutant miR-122-transfected cells formed spermatozoa-like cells. Flow cytometry of DNA content revealed a significant increase in the haploid cell population in spermatozoa-like cells derived from mutant miR-122-transfected cells as compared to those derived from miR-122-transfected cells. During induction, TNP2 and protamine mRNA and protein levels were significantly higher in mutant miR-122-transfected cells than in miR-122-transfected cells. High-throughput isobaric tags for relative and absolute quantification were used to identify and quantify the different protein expression levels in miR-122-and mutant miR-122-transfected cells. Among all the proteins analyzed, the expression of lipoproteins, for example, APOB and APOA1, showed the most significant difference between the two groups. This study illustrates that miR-122 expression is associated with abnormal sperm development. MiR-122 may influence spermatozoa-like cells by suppressing TNP2 expression and inhibiting the expression of proteins associated with sperm development.

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Sperm Chromatin Dynamics Associated with Male Fertility in Mammals

Kutchy

Doğan

Kaya

et al. 2017

Animal Models and Human Reproduction

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Identification of novel polymorphisms in the nuclear protein genes and their relationship with human sperm protamine deficiency and severe male infertility

Cited by 58 publications

References 20 publications

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

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

MicroRNA-122 Influences the Development of Sperm Abnormalities from Human Induced Pluripotent Stem Cells by Regulating TNP2 Expression

Sperm Chromatin Dynamics Associated with Male Fertility in Mammals

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