GA repeat polymorphism at the PRM2 male fertility locus

Jonckheere, Julien De; Nelson, James E.; Ginsburg, Kenneth A.; Martín, Luis Rodrigo; Krawetz, Stephen A.

doi:10.1093/hmg/3.10.1915-a

Cited by 8 publications

(4 citation statements)

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“…The variable GA repeat upstream of the transcriptional initiation start site was reported from Ceph families in earlier studies [De Jonckheere et al 1994;Schnulle et al 1994]. Both studies, as well as ours, consistently reported several GA repeat lengths, the most common length reported in all populations tested is 29bp, which suggests that the variability in the untranslated region is unlikely to account for the diminished expression of P2 in infertile patients.…”

Section: Discussionsupporting

confidence: 77%

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: Discussionsupporting

confidence: 77%

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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“…Polypurine‚polypyrimidine stretches in chromatin are hypersensitive to single strand specific nucleases, indicative of a non-B-DNA duplex conformation. Some of these sequences are highly conserved and are required for biological processes (17)(18)(19)(20)(21). It has been known for some time that oligonucleotides containing d(GA) n repeats are inefficient agents for either triplex formation or antisense approaches, partly due to the inherent tendency of these sequences to self-associate (22).…”

mentioning

confidence: 99%

Structure of d(GT)_n·d(GA)_n Sequences: Formation of Parallel Stranded Duplex DNA

Germann¹,

Kalisch²,

Sande³

1998

Biochemistry

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Alternating polypurine sequences exhibit remarkable polymorphism. In this study, we report that dGA.dGT sequences form parallel stranded duplex DNA at neutral pH. Using two model hairpins, 3'-d(GT)3-5'5'-T4(AG)3-3' (I) and 3'-d(GT)4-5'5'-T4(AG)4-3' (II), containing 5'5' linkages which direct parallel strand formation, we systematically explored the spectroscopic and thermodynamic properties of parallel stranded d(GA)n.d(GT)n. The parallel stranded hairpins are remarkably stable structures with TM's of 41.5 and 47.5 degreesC (in 0.4 M NaCl) for the shorter and longer hairpins, respectively. The van't Hoff enthalpies of 80.7 and 114 kJ mol-1 are relatively low but are comparable to a parallel stranded d(GA)n duplex. On the basis of the spectroscopic and electrophoretic characteristics, we conclude that parallel strand formation is not restricted to hairpin systems, but also readily occurs in unconstrained dimeric duplexes with the appropriate sequence homologies. Both melting curves and electrophoretic analyses of parallel stranded heteroduplexes in which the sequence enforces specific base pairing demonstrate that G-G and A-T base pairs are formed in d(GA)n.d(GT)n segments.

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“…Two studies have documented the presence of a 5′ variable length repeat (VLR) in the protamine 2 gene (De Jonckheere et al. , 1994; Schnulle et al.…”

Section: Snp Analysis In Protamine‐associated Genesmentioning

confidence: 99%

“…Two studies have documented the presence of a 5¢ variable length repeat (VLR) in the protamine 2 gene (De Jonckheere et al, 1994;Schnulle et al, 1994;Hammoud et al, 2007a). Our laboratory has recently evaluated this VLR as a possible cause of protamine abnormalities by comparing VLR lengths in patients and controls (Hammoud et al, 2007b).…”

Section: Snp Analysis In Protamine-associated Genesmentioning

confidence: 99%

The aetiology of sperm protamine abnormalities and their potential impact on the sperm epigenome

2008

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During the elongating spermatid stage of spermatogenesis, there is a step-wise replacement of nuclear histones with protamines 1 and 2. In fertile men, the ratio of protamine 1/protamine 2 (P1/P2) is within the narrow range of 0.8-1.2. Ratios above or below that range are associated with infertility, exhibiting a wide range of defects including decreased sperm counts, morphology, fertilization ability, and embryo implantation capacity. In this review, we highlight studies evaluating potential causes of abnormal protamine expression, including the sequencing of genes relevant to protamine expression in both affected patients and controls. While the variants of the protamine genes themselves do not appear to be responsible for most observed defects, variants of the Contrin gene, a transcription factor and translation repressor, appear to be contributory to some cases of abnormal expression. Additionally, we explore the potential effects of abnormal protamine replacement on the epigenome of human sperm. Ongoing studies are evaluating the role of retained histones and DNA methylation in sperm, which may be affected in sperm with aberrant protamine replacement. This important area of epigenetic research has profound clinical implications.

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GA repeat polymorphism at the PRM2 male fertility locus

Cited by 8 publications

References 0 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

Structure of d(GT)_n·d(GA)_n Sequences: Formation of Parallel Stranded Duplex DNA

The aetiology of sperm protamine abnormalities and their potential impact on the sperm epigenome

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GA repeat polymorphism at the PRM2 male fertility locus

Cited by 8 publications

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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

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

Structure of d(GT)n·d(GA)n Sequences: Formation of Parallel Stranded Duplex DNA

The aetiology of sperm protamine abnormalities and their potential impact on the sperm epigenome

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Structure of d(GT)_n·d(GA)_n Sequences: Formation of Parallel Stranded Duplex DNA