HUMAN MALE INFERTILITY: GENETIC STUDIES OF AZOOSPERMIA

本申请的广泛的长期目标是探索 遗传缺陷在人类男性不育中的作用。以百万 其他方面都很健康的美国男性，精子发生是定性的， 或数量上有缺陷，导致不育。大 大多数这样的正常男性，精子发生的原因 目前还无法查明缺陷。许多研究都集中在 感染因子，免疫过程，精索静脉曲张， 化学损伤或其它生理或环境因素。虽然 遗传缺陷可以选择性地 损害精子发生（不引起其他疾病）， 很少有直接证据表明这一点。因此，尽管 人们普遍认为，遗传变异在这种常见的疾病中起着重要作用。 癌症、心脏病、糖尿病和高血压等疾病， 在传统思维中， 关于精子发生受损 本申请将 探索基因异常是导致 其他方面正常的男性精子发生缺陷。 更具体地，本申请的目标是测试本发明。 无精子因子（AZF）基因缺失假说 Y染色体长臂是严重生精障碍的常见原因。 人类男性的缺陷AZF基因将通过遗传学鉴定 严重生精缺陷男性的缺失分析。结构， 功能和基因的表达将被检查。的可能性 基因中的细微突变会导致 将探索缺陷。基因的从头缺失的机制 AZF基因在人群中出现频率高， 研究了

The broad, long-term objective of the present application is to explore the role of genetic defects in human male infertility. In millions of American men who are otherwise healthy, spermatogenesis is qualitatively or quantitatively defective, and infertility results. In the great majority of such otherwise normal men, the cause of the spermatogenesis defect cannot be pinpointed at present. Numerous studies have focused on the possible role of infectious agents, immune processes, varicoceles, chemical insults, or other physiologic or environmental factors. While it has always been formally possible that genetic defects could selectively impair spermatogenesis (without causing disease elsewhere), there has been little direct evidence that this is the case. As a result, though it is widely accepted that genetic variation plays a major role in such common diseases as cancer, heart disease, diabetes, and hypertension, genetic explanations have not featured prominently in the conventional thinking with regard to impaired spermatogenesis. The present application will explore the possibility that genetic abnormalities are a significant cause of spermatogenic defects in otherwise normal men. More specifically, the goal of the present application is to test the hypothesis that deletion of the "Azoospermia Factor" (AZF) gene on the long arm of the Y chromosome is a frequent cause of severe spermatogenic defects in human males. The AZF gene will be identified by genetic deletion analysis of men with severe spermatogenic defects. The structure, function, and expression of the gene will be examined. The possibility that subtle mutations within the gene cause less severe spermatogenic defects will be explored. The mechanisms by which de novo deletions of the AZF gene occur at high frequency in human populations will be investigated.