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Guixiang Ji
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Lifeng Yan Nanjing Institute of Environmental Sciences/Key Laboratory of Pesticide Environmental Assessment and Pollution Control, State Key Laboratory of Reproductive Medicine, Ministry of Environmental Protection, Nanjing 210042, People's Republic of China and

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Wei Liu Nanjing Institute of Environmental Sciences/Key Laboratory of Pesticide Environmental Assessment and Pollution Control, State Key Laboratory of Reproductive Medicine, Ministry of Environmental Protection, Nanjing 210042, People's Republic of China and

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Cong Huang Nanjing Institute of Environmental Sciences/Key Laboratory of Pesticide Environmental Assessment and Pollution Control, State Key Laboratory of Reproductive Medicine, Ministry of Environmental Protection, Nanjing 210042, People's Republic of China and

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Aihua Gu Nanjing Institute of Environmental Sciences/Key Laboratory of Pesticide Environmental Assessment and Pollution Control, State Key Laboratory of Reproductive Medicine, Ministry of Environmental Protection, Nanjing 210042, People's Republic of China and

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Xinru Wang Nanjing Institute of Environmental Sciences/Key Laboratory of Pesticide Environmental Assessment and Pollution Control, State Key Laboratory of Reproductive Medicine, Ministry of Environmental Protection, Nanjing 210042, People's Republic of China and

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The DNA double-strand breaks (DSBs) repair pathway plays a critical role in repairing double-strand breaks, and genetic variants in DSBs repair pathway genes are potential risk factors for various diseases. To test the hypothesis that polymorphisms in DSBs genes are associated with susceptibility to male infertility, we examined 11 single nucleotide polymorphisms in eight key DSBs genes (XRCC3, XRCC2, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in 580 infertility cases and 580 controls from a Chinese population-based case–control study (NJMU Infertility Study). Genotypes were determined using the OpenArray platform, and sperm DNA fragmentation was detected using the TUNEL assay. The adjusted odds ratio (OR) and 95% CI were estimated using logistic regression. The results indicate that LIG4 rs1805388 (Ex2+54C>T, Thr9Ile) T allele could increase the susceptibility to male infertility (adjusted OR=2.78; 95% CI, 1.77–4.36 for TT genotype; and adjusted OR=1.58; 95% CI, 1.77–4.36 for TC genotype respectively). In addition, the homozygous variant genotype GG of RAG1 rs2227973 (A>G, K820R) was associated with a significantly increased risk of male infertility (adjusted OR, 1.44; 95% CI, 1.01–2.04). Moreover, linear regression analysis revealed that carriers of LIG4 rs1805388 or RAG1 rs2227973 variants had a significantly higher level of sperm DNA fragmentation and that T allele carriers of LIG4 rs1805388 also had a lower level of sperm concentration when compared with common homozygous genotype carriers. This study demonstrates, for the first time, to our knowledge, that functional variants of RAG1 rs2227973 and LIG4 rs1805388 are associated with susceptibility to male infertility.

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Yan Xu Medical School of Fudan University, Center for Biomedical Research, The Rockefeller University, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Department of Anatomy, Shanghai, China

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Miao Liu Medical School of Fudan University, Center for Biomedical Research, The Rockefeller University, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Department of Anatomy, Shanghai, China

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Yi-hua Gu Medical School of Fudan University, Center for Biomedical Research, The Rockefeller University, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Department of Anatomy, Shanghai, China

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Xiao-feng Jia Medical School of Fudan University, Center for Biomedical Research, The Rockefeller University, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Department of Anatomy, Shanghai, China

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Yong-Mei Chen Medical School of Fudan University, Center for Biomedical Research, The Rockefeller University, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Department of Anatomy, Shanghai, China

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Michelle Santos Medical School of Fudan University, Center for Biomedical Research, The Rockefeller University, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Department of Anatomy, Shanghai, China

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Ai-Zhen Wu Medical School of Fudan University, Center for Biomedical Research, The Rockefeller University, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Department of Anatomy, Shanghai, China

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Xiao-dong Zhang Medical School of Fudan University, Center for Biomedical Research, The Rockefeller University, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Department of Anatomy, Shanghai, China

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Hui-Juan Shi Medical School of Fudan University, Center for Biomedical Research, The Rockefeller University, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Department of Anatomy, Shanghai, China
Medical School of Fudan University, Center for Biomedical Research, The Rockefeller University, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Department of Anatomy, Shanghai, China

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Ching-Ling C Chen Medical School of Fudan University, Center for Biomedical Research, The Rockefeller University, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Department of Anatomy, Shanghai, China
Medical School of Fudan University, Center for Biomedical Research, The Rockefeller University, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Department of Anatomy, Shanghai, China

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With tetraspanning topology, members of the membrane-spanning four-domain subfamily A (MS4A) may facilitate signaling or ion channel functions in many tissues. In this study, we report the cloning of a full-length cDNA from rat testis, designated Ms4a14 (Sp3111), which encodes the MS4A protein with 1139 amino acid residues. In situ hybridization and immunohistochemical analyses indicate that Ms4a14 is predominantly expressed from round spermatids to spermatozoa at specific stages in the rat testis at both the mRNA and protein level. Immunofluorescence analysis revealed that MS4A14 (SP3111) is located in the acrosome and the midpiece of the flagellum in mature sperm. Previously, we explored and reported the involvement of MS4A14 in reproductive functions, using antibody blockage during IVF and a transgenic RNA interference method in a mouse model. Our results suggested that MS4A14 is involved in fertilization and zygote division. As MS4A14 protein exists in mammals, such as humans, cows, dogs, and rodents, MS4A14 may play a ubiquitous role in mammalian reproduction.

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