HUMAN MALE INFERTILITY: GENETIC STUDIES OF AZOOSPERMIA

本应用程序的广泛、长期目标是探索 基因缺陷在人类男性不育中的作用。数以百万计的 在其他方面都很健康的美国男性，精子发生在质量上 或在数量上有缺陷，导致不孕。在伟大的 大多数这样的正常男性，精子发生的原因 目前还不能准确地指出缺陷。许多研究都集中在 感染因素、免疫过程、精索静脉曲张、 化学侮辱，或其他生理或环境因素。当它 在形式上一直是可能的，基因缺陷可能会选择性地 损害精子发生(不会在其他地方引起疾病)， 几乎没有直接证据表明情况就是这样。因此，尽管它是 人们普遍认为遗传变异在这种常见的疾病中起主要作用 癌症、心脏病、糖尿病和高血压等疾病，遗传性 解释在传统思维中没有得到突出的体现。 关于精子发生受损的问题。本申请将 探索基因异常是重要原因的可能性 其他正常男性的生精缺陷。 更具体地说，本应用程序的目标是测试 假设“无精子因子”(AZF)基因的缺失 Y染色体长臂是严重生精的常见原因 人类男性的缺陷。AZF基因将通过遗传鉴定 严重生精缺陷男性的缺失分析。这个结构， 将检测该基因的功能和表达情况。这种可能性 基因中的细微突变会导致不那么严重的精子生成 将探索缺陷。从头删除的机制 AZF基因在人类群体中出现的频率将很高 调查过了。

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.