Two single nucleotide polymorphisms in PRDM9 (MEISETZ) gene may be a genetic risk factor for Japanese patients with azoospermia by meiotic arrest

  • Toshinobu Miyamoto
  • Eitetsu Koh
  • Naoko Sakugawa
  • Hisashi Sato
  • Hiroaki Hayashi
  • Mikio Namiki
  • Kazuo Sengoku



To investigate whether defects in human PRDM9, CDK2 and PSMC3IP are associated with azoospermia Mutational analysis was performed in Japanese patients with azoospermia caused by meiotic arrest.


Mutational screening of the coding regions of human PRDM9, CDK2 and PSMC3IP was done by direct sequencing using genomic DNA from 18 Japanese patients. Statistical analysis of the detected coding single nucleotide polymorphisms (cSNPs) in patients and normal control men was then carried out.


One cSNP was detected in CDK2 and PSMC3IP. There were no significant differences in genotype distribution and allele frequencies between the patient and control groups in these two genes. However, three novel cSNPs were detected in the PRDM9. The genotype and allele frequencies of heterozygotes in SNP2 and SNP3 of PRDM9 were significantly higher in the patient group than in the control group.


We found a possible association between PRDM9 and azoospermia by meiotic arrest.


Azoospermia CDK2 PRDM9 PSMC3IP SNP 



This study was supported by Grants-in-Aid for Scientific Research (No. 19591887 and 20591902) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Ministry of Health, Labour and Welfare of Japan.


  1. 1.
    Reijo R, Lee TY, Salo P, Alagappan R, Brown LG, Rosenberg M, et al. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet. 1995;10:383–93. doi: 10.1038/ng0895-383.PubMedCrossRefGoogle Scholar
  2. 2.
    Elliott DJ, Millar MR, Oghene K, Ross A, Kiesewetter F, Pryor J, et al. Expression of RBM in the nuclei of human germ cells is dependent on a critical region of the Y chromosome long arm. Proc Natl Acad Sci USA. 1997;94:3848–53. doi: 10.1073/pnas.94.8.3848.PubMedCrossRefGoogle Scholar
  3. 3.
    Sun C, Skaletsky H, Birren B, Devon K, Tang Z, Silber S, et al. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nat Genet. 1999;23:429–32. doi: 10.1038/70539.PubMedCrossRefGoogle Scholar
  4. 4.
    Matzuk MM, Lamb DJ. Genetic dissection of mammalian fertility pathway. Nat Med. 2002;8(suppl 1):S41–9. doi: 10.1038/nm0102-41.Google Scholar
  5. 5.
    Miyamoto T, Hasuike S, Yogev L, Maduro MR, Ishikawa M, Westphal H, et al. Azoospermia in patients heterozygous for a mutation in SYCP3. Lancet. 2003;362:1714–9. doi: 10.1016/S0140-6736(03)14845-3.PubMedCrossRefGoogle Scholar
  6. 6.
    Nakamura Y, Kitamura M, Nishimura K, Koga M, Kondoh N, Takeyama M, et al. Chromosomal variants among 1,790 infertile men. Int J Urol. 2001;8:49–52. doi: 10.1046/j.1442-2042.2001.00242.x.PubMedCrossRefGoogle Scholar
  7. 7.
    Sato H, Miyamoto T, Yogev L, Namiki M, Koh E, Hayashi H, et al. Polymorphic alleles of the human MEI1 gene are associated with human azoospermia by meiotic arrest. J Hum Genet. 2006;51:533–40. doi: 10.1007/s10038-006-0394-5.PubMedCrossRefGoogle Scholar
  8. 8.
    Nasmyth K. Segregating sister genomes: the molecular biology of chromosome separation. Science. 2002;297:559–65. doi: 10.1126/science.1074757.PubMedCrossRefGoogle Scholar
  9. 9.
    Yoshida K, Kondoh G, Matsuda Y, Habu T, Nishimune Y, Morita T. The mouse RecA-like gene Dmc1 is required for homologous chromosome synapsis during meiosis. Mol Cell. 1998;1:707–18. doi: 10.1016/S1097-2765(00)80070-2.PubMedCrossRefGoogle Scholar
  10. 10.
    Pittman DL, Cobb J, Schimenti KJ, Wilson LA, Cooper DM, Brignull E, et al. Meiotic prophase arrest with failure of chromosome synapsis in mice deficient for Dmc1, a germline-specific RecA homolog. Mol Cell. 1998;1:697–705. doi: 10.1016/S1097-2765(00)80069-6.PubMedCrossRefGoogle Scholar
  11. 11.
    Edelmann W, Cohen PE, Kneitz B, Winand N, Lia M, Heyer J, et al. Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nat Genet. 1999;21:123–7. doi: 10.1038/5075.PubMedCrossRefGoogle Scholar
  12. 12.
    Baudat F, Manova K, Yuen JP, Jasin M, Keeney S. Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Mol Cell. 2000;6:989–98. doi: 10.1016/S1097-2765(00)00098-8.PubMedCrossRefGoogle Scholar
  13. 13.
    Kneitz B, Cohen PE, Avdievich E, Zhu L, Kane MF, Hou H Jr, et al. MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice. Genes Dev. 2000;14:1085–97.PubMedGoogle Scholar
  14. 14.
    Romanienko PJ, Camerini-Otero RD. The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol Cell. 2000;6:975–87. doi: 10.1016/S1097-2765(00)00097-6.PubMedCrossRefGoogle Scholar
  15. 15.
    Yuan L, Liu JG, Zhao J, Brundell E, Daneholt B, Hoog C. The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Mol Cell. 2000;5:73–83. doi: 10.1016/S1097-2765(00)80404-9.PubMedCrossRefGoogle Scholar
  16. 16.
    Crackower MA, Kolas NK, Noguchi J, Sarao R, Kikuchi K, Kaneko H, et al. Essential role of Fkbp6 in male fertility and homologous chromosome pairing in meiosis. Science. 2003;300:1291–5. doi: 10.1126/science.1083022.PubMedCrossRefGoogle Scholar
  17. 17.
    Hayashi K, Yoshida K, Matsui Y. A histone H3 methyltransferase controls epigenetic events required for meiotic prophase. Nature. 2005;438:374–8. doi: 10.1038/nature04112.PubMedCrossRefGoogle Scholar
  18. 18.
    Ortega S, Prieto I, Odajima J, Martin A, Dubus P, Sotillo R, et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet. 2003;35:25–31. doi: 10.1038/ng1232.PubMedCrossRefGoogle Scholar
  19. 19.
    Petukhova GV, Romanienko PJ, Camerini-Otero RD. The Hop2 protein has a direct role in promoting interhomolog interactions during mouse meiosis. Dev Cell. 2003;5:927–36. doi: 10.1016/S1534-5807(03)00369-1.PubMedCrossRefGoogle Scholar
  20. 20.
    Tsujimura A, Takahara S, Kitamura M, Miura H, Koga M, Sada M, et al. HLA-DR antigen and HLA-DRB1 genotyping with nonobstructive azoospermia in Japan. J Androl. 1999;20:545–50.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Toshinobu Miyamoto
    • 1
    • 3
  • Eitetsu Koh
    • 2
  • Naoko Sakugawa
    • 1
  • Hisashi Sato
    • 1
  • Hiroaki Hayashi
    • 1
  • Mikio Namiki
    • 2
  • Kazuo Sengoku
    • 1
  1. 1.Department of Obstetrics and GynecologyAsahikawa Medical CollegeAsahikawaJapan
  2. 2.Department of Integrated Cancer Therapy and UrologyKanazawa University Graduate School of Medical ScienceKanazawaJapan
  3. 3.Department of Obstetrics and GynecologyAsahikawa Medical CollegeAsahikawaJapan

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