Sato Hisashi, Miyamoto Toshinobu, Yogev Leah, Namiki Mikio, Koh Eitesu, Hayashi Hiroaki, Sasaki Yoshihito, Ishikawa Mutsuo, Lamb Dolores J, Matsumoto Naomichi, Birk Ohad S, Niikawa Norio, Sengoku Kazuo
Department of Obstetrics and Gynecology, Asahikawa Medical College, 2-1-1-1 Midorigaokahigashi, Asahikawa, 078-8510, Japan.
Institute for the Study of Fertility, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
J Hum Genet. 2006;51(6):533-540. doi: 10.1007/s10038-006-0394-5. Epub 2006 May 9.
Genetic mechanisms are implicated as a cause of some male infertility, yet are poorly understood. Mouse meiotic mutant mei1 (meiosis defective 1) was isolated by a screening of infertile mice. Male mei1 mice have azoospermia due to meiotic arrest, and the mouse Mei1 gene is responsible for the mei1 phenotype. To investigate whether human MEI1 gene defects are associated with azoospermia by meiotic arrest, we isolated the human MEI1 cDNA based on the mouse Mei1 amino acid sequence. MEI1 is expressed specifically in the testis. Mutational analysis by direct sequencing of all MEI1 coding regions was performed in 27 men (13 European Americans, 13 Israeli and 1 Japanese) having azoospermia due to complete early meiotic arrest. This identified four novel, coding single-nucleotide-polymorphisms (cSNPs), i.e., SNP1 (T909G), SNP2 (A1582G), SNP3 (C1791A) and SNP4 (C2397T) in exons 4, 8, 9 and 14, respectively. Using these cSNPs, an association study was carried out between 26 non-Japanese patients with azoospermia and two sets of normal control men (61 normal European Americans and 60 Israelis). Consequently, SNP3 and SNP4 were shown to be associated with azoospermia among European Americans (P =0.0289 and P =0.0299 for genotype and allele frequencies at both the polymorphic sites, respectively), although no such association was observed among Israelis (P >0.05). Haplotype estimation revealed that the frequencies of SNP3-SNP4 (C-T), SNP3-SNP4 (A-C) and SNP3-SNP4 (A-T) were higher in the European American patients, and the frequency of SNP3-SNP4 (A-T) was also higher than in both control groups. These results suggest that MEI1 may play a role in meiosis during spermatogenesis, especially in European Americans.
遗传机制被认为是某些男性不育症的病因之一，但目前对其了解甚少。通过对不育小鼠进行筛选，分离出了小鼠减数分裂突变体mei1（减数分裂缺陷1）。雄性mei1小鼠由于减数分裂停滞而无精子症，小鼠Mei1基因负责mei1表型。为了研究人类MEI1基因缺陷是否与减数分裂停滞导致的无精子症相关，我们根据小鼠Mei1氨基酸序列分离出了人类MEI1 cDNA。MEI1仅在睾丸中特异性表达。对27名因早期减数分裂完全停滞而患有无精子症的男性（13名欧裔美国人、13名以色列人和1名日本人）进行了所有MEI1编码区的直接测序突变分析。这确定了四个新的编码单核苷酸多态性（cSNP），即分别在外显子4、8、9和14中的SNP1（T909G）、SNP2（A1582G）、SNP3（C1791A）和SNP4（C2397T）。利用这些cSNP，在26名非日本无精子症患者和两组正常对照男性（61名正常欧裔美国人和60名以色列人）之间进行了关联研究。结果显示，SNP3和SNP4与欧裔美国人的无精子症相关（两个多态性位点的基因型和等位基因频率分别为P =0.0289和P =0.0299），而在以色列人中未观察到这种关联（P >0.05）。单倍型估计显示，SNP3-SNP4（C-T）、SNP3-SNP4（A-C）和SNP3-SNP4（A-T）在欧裔美国患者中的频率较高，SNP3-SNP4（A-T）的频率也高于两个对照组。这些结果表明，MEI1可能在精子发生过程中的减数分裂中起作用，尤其是在欧裔美国人中。
