Hum. Reprod. Advance Access originally published online on May 16, 2008
Human Reproduction 2008 23(11):2611-2613; doi:10.1093/humrep/den063
Letters to the Editor |
Differences in gonadotropin-regulated testicular helicase (GRTH/DDX25) single nucleotide polymorphism between Japanese and Chinese populations
1 Section on Molecular Endocrinology, Endocrinology and Reproduction Research Branch, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institute of Health, Bethesda, MD 20892, USA 2 Department of Urology, Kanazawa University School of Medicine, Ishikawa, Japan
3 Correspondence address. E-mail: morrisch{at}mail.nih.gov
We would like to make a comment on the article by Zhoucun et al. (2006)
published in Human Reproduction, entitled ‘Single nucleotide polymorphisms of the gonadotropin-regulated testicular helicase (GRTH) gene may be associated with the human spermatogenesis impairment’. This specifically relates to the conclusion about their finding that allele T of c.852C 
T polymorphism of the GRTH gene might increase the risk of impaired spermatogenesis in humans. In contrast to their patient group of infertile males with idiopathic azoospermia or oligozoospermia from West China, we did not find any statistical significance of this allele change in Japanese men with non-obstructive azoospermia (NOA) (Table I). Therefore, this particular single nucleotide polymorphism (SNP) might be an ethnic link to male infertility in Chinese patients from West China.
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The most relevant observation in this report was the silent mutation (Cys) located in exon 10 (c.852C
T; should be nt 1194 instead—see below) of the GRTH gene in a Chinese population. The investigators proposed that because the nucleotide is located just 7 bp upstream from the donor site of the pre-RNA splice and is part of the consensus binding motif (TG852CGCCCGA, mutation position is underlined) of splicing factor 2 (SF2/ASF) (Cartegni et al., 2003; Sanford et al., 2005), the change in the allele from C to T might abolish or decrease SF2/ASF activity and reduce GRTH/DDX25 gene expression. Since we have previously demonstrated that GRTH is a multifunctional RNA helicase involved in gene-specific mRNA transport and protein translation during spermatogenesis (Tsai-Morris et al., 2004; Sheng et al., 2006; Dufau and Tsai-Morris, 2007), the proposed reduction of its gene expression through the SNP of C to T at nt 1194 could be a potential important mechanism for impaired spermatogenesis found in humans.
For clarification purposes, the nucleotide position of C to T at nt 852 reported by Zhoucun et al. was based on the second ATG codon (nt 343) not the first codon (nt 1) of GRTH/DDX25 (Sheng et al., 2003). Thus, the actual position of this SNP is nt 1194. Specifically, the first codon is primarily utilized in germ cells to generate a 56/61 kDa protein species, whereas the second ATG is the primary site utilized in Leydig cells and yields the 42/46 kDa protein species. The 61 kDa species are the phosphorylated forms of the 56 kDa species (Sheng et al., 2006). The same is applicable to the SNP at nt 927 in exon 11 which should be nt 1269.
Because GRTH is essential for spermatid development and the completion of spermatogenesis in mice (Tang et al., 1999; Tsai-Morris et al., 2004; Dufau and Tsai-Morris, 2007), we are very interested to investigate potential GRTH mediated action in the male infertility. Our recent SNP scanning study (Tsai-Morris et al., 2007) has identified a polymorphic missense mutation at exon 8 (nt 725 G to C., aa 242, R to H) and a silent mutation at exon 11 (nt 1245, C to G., aa 415, L to L) that might be associated with NOA in a Japanese population. The unique heterozygous missense mutation Arg242His in exon 8 could impact the post-transcriptional modification of the expressed GRTH protein. The mutant protein does not undergo phosphorylation and consequently could affect translational regulation of essential genes during germ cells development (Sheng et al., 2006; Dufau and Tsai-Morris, 2007). In this study, we did not detect the SNP at nt 1194 (Tsai-Morris et al., 2007) because the 3' reversed primer used overlapped the donor site of exon 10. After repeating the SNP scanning on exon 10 with new primer sets flanking the exon sequence of total 508 bp, we observed that the allele frequency of either C or T was comparable between normal and NOA in Japanese patients with P > 0.38, in contrast to Chinese patients with P < 0.034 (Table I). Interestingly, it was also noted that the SNPs of exons 8 and 11 found in Japanese patients (Tsai-Morris et al., 2007) were not apparent in the Chinese patients (Zhoucun et al., 2006). Because of these differences found between the Chinese and Japanese populations, we propose that SNPs of GRTH gene might be associated with an ethnic background of male infertility among Asian men.
References
Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR. ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res (2003) 31:3568–3571.
Dufau ML, Tsai-Morris CH. Gonadotropin-regulated testicular helicase (GRTH/DDX25): an essential regulator of spermatogenesis. Trends Endocrinol Metab (2007) 18:314–320.[CrossRef][Web of Science][Medline]
Sanford JR, Ellis J, Caceres JF. Multiple roles of arginine/serine-rich splicing factors in RNA processing. Biochem Soc Trans (2005) 33:443–446.[CrossRef][Web of Science][Medline]
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Tsai-Morris CH, Sheng Y, Lee E, Lei KJ, Dufau ML. Gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) is essential for spermatid development and completion of spermatogenesis. Proc Natl Acad Sci USA (2004) 101:6373–6378.
Tsai-Morris CH, Koh E, Sheng Y, Maeda Y, Gutti R, Namiki M, Dufau ML. Polymorphism of the GRTH/DDX25 gene in normal and infertile Japanese men: a missense mutation associated with loss of GRTH phosphorylation. Mol Hum Reprod (2007) 12:887–892.
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