Polymorphic alleles of the human MEI1 gene are associated with human azoospermia by meiotic arrest
Polymorphic alleles of the human MEI1 gene are associated with human azoospermia by meiotic arrest
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DOI：
10.1007/s10038-006-0394-5
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发表时间：
2006-05
影响因子：
3.5
通讯作者：
Hisashi Sato;T. Miyamoto;L. Yogev;M. Namiki;E. Koh;H. Hayashi;Yoshihito Sasaki;M. Ishikawa;D. Lamb;N. Matsumoto;O. Birk;N. Niikawa;K. Sengoku
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文献类型：
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作者：
Hisashi Sato;T. Miyamoto;L. Yogev;M. Namiki;E. Koh;H. Hayashi;Yoshihito Sasaki;M. Ishikawa;D. Lamb;N. Matsumoto;O. Birk;N. Niikawa;K. Sengoku
遗传机制被认为是一些男性不育的原因，但人们对其了解甚少。通过对不育小鼠的筛选，分离到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止而无精子症，小鼠mei1基因负责mei1表型。为了研究人类MEI1基因缺陷是否通过减数分裂阻滞与无精子症相关，我们基于小鼠MEI1氨基酸序列分离了人类MEI1 cDNA。MEI1在睾丸中特异表达。对27名因减数分裂完全早期停止而无精子症的男性（13名欧美人、13名以色列人和1名日本人）进行了所有MEI1编码区直接测序的突变分析。该方法鉴定了4个新的编码单核苷酸多态性（csnp），即SNP1 （T909G）、SNP2 （A1582G）、SNP3 （C1791A）和SNP4 (C2397T)，分别位于外显子4、8、9和14。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名正常的欧洲裔美国人和60名以色列人）之间进行了一项关联研究。因此，SNP3和SNP4被证明与欧洲裔美国人的无精子症有关（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），尽管在以色列人中没有观察到这种关联（P < 0.05）。单倍型估计显示，在欧美患者中SNP3-SNP4 （C-T）、SNP3-SNP4 （A-C）和SNP3-SNP4 （A-T）的频率更高，且SNP3-SNP4 （A-T）的频率也高于两组对照组。这些结果表明，MEI1可能在精子发生过程中起减数分裂作用，特别是在欧美人。
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), ie, 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.