Yong E L, Lim J, Wang Q, Mifsud A, Ong Y C, Sim C K
Department of Obstetrics and Gynecology, National University of Singapore, Singapore.
Ann Acad Med Singap. 2000 May;29(3):396-400.
Although infertility affects about 5% of the male population, its cause in most cases is uncertain. Normal spermatogenesis depends on a sequential cascade of genetic events triggered by factors encoded by the sex chromosomes. To determine the contribution of genetic aberrations to male infertility, the X-linked androgen receptor gene and the Y-chromosome were examined for mutations in a large cohort of infertile men.
Screening of the androgen receptor (AR) gene for single-stranded conformation polymorphisms, confirmation by DNA sequencing, structure-function studies with androgen-responsive reporter genes and chimeric-protein constructs were performed. Y-chromosome microdeletions screening was done with multiplex polymerase chain reaction (PCR) analyses.
Genetic screening of over 400 patients and controls showed that defects in the androgen receptor gene lead to the production of dysfunctional receptor protein in 15% of males with abnormally low sperm production. The dozens of mutations and polymorphisms uncovered were associated with reduced intrinsic androgen receptor activity and involve principally two regions of the androgen receptor. Gene-transfer experiments implicated defective intermolecular protein-protein interactions with coactivator molecules as the cause of reduced receptor function. Submicroscopic deletions of the Y-chromosome were also been detected in about 6% of patients with severely reduced spermatogenesis. The deleted segments encoded RNA-binding proteins of unknown function and are not linked to defects in the androgen receptor.
Mutations and polymorphisms of the AR, and Y-microdeletions cause defective sperm production and male infertility in about 20% of subfertile men. These traits can be transmitted to progeny, and counselling can be offered to affected families. Clarification of the molecular mechanisms of pathogenesis has led to rational hormonal therapy.
尽管不育症影响着约5%的男性人口，但在大多数情况下其病因尚不确定。正常的精子发生依赖于由性染色体编码的因子触发的一系列连续的遗传事件。为了确定基因畸变对男性不育症的影响，我们在一大群不育男性中检测了X连锁雄激素受体基因和Y染色体的突变情况。
对雄激素受体（AR）基因进行单链构象多态性筛查，通过DNA测序进行确认，利用雄激素反应性报告基因和嵌合蛋白构建体进行结构-功能研究。采用多重聚合酶链反应（PCR）分析进行Y染色体微缺失筛查。
对400多名患者和对照的基因筛查显示，雄激素受体基因缺陷导致15%精子生成异常少的男性产生功能失调的受体蛋白。发现的几十种突变和多态性与雄激素受体内在活性降低有关，主要涉及雄激素受体的两个区域。基因转移实验表明，与共激活分子的分子间蛋白质-蛋白质相互作用缺陷是受体功能降低的原因。在约6%精子生成严重减少的患者中也检测到Y染色体亚显微缺失。缺失片段编码功能未知的RNA结合蛋白，且与雄激素受体缺陷无关。
AR的突变和多态性以及Y微缺失在约20%的不育男性中导致精子生成缺陷和男性不育。这些特征可遗传给后代，可为受影响的家庭提供咨询。对发病机制分子机制的阐明已导致合理的激素治疗。
