Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nucleotide-excision repair (NER) system is crucial for the removal of bulky DNA adducts during spermatogenesis. Dysfunction of its repair capacity is likely related to the increased susceptibility to DNA damage. In this study, four polymorphisms in NER pathway (XPA(-4) G/A, ERCC1 C8092A, XPD Lys751Gln and XPF Ser835Ser) were selected to evaluate their potential impact on sperm DNA damage and male infertility. Genotypes were determined by PCR-restriction fragment length polymorphism. Sperm DNA damage was evaluated by TdT-mediated dUDP nick-end labelling assay. A case-only study of 620 infertile men found a significant association between XPA(-4) G/A polymorphism and sperm DNA damage. Individuals with the XPA(-4) A allele showed more sperm DNA damage and lower sperm concentration than G allele carriers. Further analysis, including 620 patients and 385 controls, revealed a 1.52-fold risk (95% CI 1.08-2.02) of developing male infertility in the XPA(-4) AA carriers compared with noncarriers. Luciferase assay verified that the promoter with the XPA(-4) A allele had a lower transcriptional activity than that with the G allele. These data provide the first evidence that -4 G/A polymorphism in XPA promoter alters its transcriptional activity and, thus, might contribute to sperm DNA damage and male infertility. Sperm DNA integrity is essential for the accurate transmission of genetic information. To our knowledge, few studies have elucidated the effect of DNA repair gene single-nucleotide polymorphisms on sperm DNA integrity, although the DNA repair system is indispensable in maintaining genetic stability and normal spermatogenesis. In this original study, we evaluated the potential impact of the polymorphisms in the nucleotide-excision repair pathway on the risk of sperm DNA damage based on 620 infertile patients and 385 controls, and provided the first evidence that -4 G/A polymorphism in the promoter for the xeroderma pigmentosum group A gene altered its transcriptional activity, which might contribute to sperm DNA damage and male infertility.
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PMID:Polymorphisms of nucleotide-excision repair genes may contribute to sperm DNA fragmentation and male infertility. 2086 14

Xeroderma pigmentosum (XP) involves a defect in the initial step of nucleotide excision repair (NER) and consists of eight genetic complementation groups (groups A-G and a variant). XP group A (XPA) patients have a high incidence of UV-induced skin tumors, immature testicular development, and neurological symptoms. In an earlier study, we have shown that XP group A (Xpa) gene-knockout mice (Xpa-/- mice) were highly sensitive to UV-induced skin carcinogenesis with a defect in NER and were highly susceptibility to spontaneous tumorigenesis with impaired spermatogenesis. However, the pathology of impaired spermatogenesis in Xpa-/- mice is unknown. To unravel the underlying pathology, we made a concerted effort using the testis of 3-month-old Xpa-/- mice. We found many large vacuoles in the seminiferous tubules of 3-month old Xpa-/- mice, while there were no large vacuoles in that of Xpa+/+ mice. Immunohistochemistry of microtubule-associated protein 1 light chain 3 (LC3), an autophagosome marker, showed degenerating cells with intense signal of LC3 in the seminiferous tubules, and immunoblotting revealed induction of LC3-II in the 3-month-old Xpa-/- mice. The results of the present study suggest autophagy induction as the possible mechanism underlying the impaired spermatogenesis in Xpa-/- mice. Therefore, Xpa-/- mice could be a useful model for investigating aging and male infertility with low expression of XPA.
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PMID:Autophagy induction on impaired spermatogenesis of xeroderma pigmentosum group A gene-deficient mice. 3307 Dec 59