GENETIC CONTROL OF HUMAN GONADAL DIFFERENTIATION

Y染色体在男性性别决定中的重要作用 已经建立，触发这一过程的基因被称为 睾丸决定因子（TDF）。 对人类TDF基因座的研究 被促成的存在两个条件，46，XY完成 性腺发育不全（患有前列腺癌的受试者缺乏睾丸分化） 男性核型）和46，XX男性（受试者睾丸的发育 具有明显的女性核型）。 TDF基因座已被定位到 Y染色体短臂的末端区域。 候选基因 Goodfellow及其同事已从该位点克隆了TDF， 被称为性别决定区Y（SRY）。 几行 有证据表明，SRY确实是TDF。SRY基因是 DNA结合蛋白家族，称为高迁移率族（HMG）。 最近的研究表明，HMG蛋白可能影响基因转录， 结合到序列特异性位点，并通过改变 DNA. 因此，SRY可能通过以下方式触发睾丸决定： 与序列特异性DNA位点结合。 然而，生理约束力 SRY在人类基因组中的位点和SRY的作用方式是 未知 我们的主要假设是SRY基因产物控制着 通过启动一连串基因的激活来决定男性的性别。 本建议的具体目标是：1）确定具体的性、生殖、健康和青年 结合位点; 2）确定SRY的影响 对DNA构象和转录激活的影响; 3） 确定SRY基因中自然发生的突变的影响 对SRY蛋白与其特异性结合 网站. 4)进一步探讨46，XY性腺发育的遗传基础 通过研究SRY基因突变， 受影响的个人，并通过在运动学中进行连锁分析， 遗传性性腺发育不全 这些研究将提供新的 信息，并成为未来研究的基础， 正常睾丸所必需的基因之间复杂的相互作用 保持战略定力 他们也将允许更好地了解异常 性别分化

The essential role of the Y chromosome in primary male sex determination is well established and the gene that triggers this process is termed the testis-determining factor (TDF). Studies of the TDF locus in man have been facilitated by the existence of two conditions, 46,XY complete gonadal dysgenesis (lack of testis differentiation in subjects with a male karyotype), and 46,XX maleness (development of testes in subjects with an apparently female karyotype). The TDF locus has been mapped to the distal region of the short arm of the Y chromosome. A candidate gene for TDF has been cloned from this locus by Goodfellow and co-workers, and has been called sex-determining region Y (SRY). Several lines of evidence indicate that SRY is indeed the TDF. The SRY gene is a member of a family of DNA binding proteins, termed the high mobility group (HMG). Recent studies show that HMG proteins may influence gene transcription by binding to sequence specific sites and by changing the conformation of DNA. Hence, it is likely that SRY triggers testis determination by binding to sequence specific DNA sites. However, the physiologic binding site(s) of SRY in the human genome and the mode of action of SRY are unknown. Our principal hypothesis is that the SRY gene product controls male sex determination by initiating activation of a cascade of genes. The specific aims of this proposal are: 1) To identify specific SRY binding sites in the human genome; 2) to determine the influence of SRY on the conformation of DNA and on transcriptional activation; 3) To determine the influence of naturally occurring mutations in the SRY gene on the ability of SRY protein to interact with its specific binding sites. 4) To investigate further the genetic basis of 46,XY gonadal dysgenesis in additional subjects by investigating SRY mutations in affected individuals and by performing linkage analysis in kindreds with inherited forms of gonadal dysgenesis. These studies will provide new information and be the foundation for future studies to examine the complex interplay of the genes that are necessary for normal testis determination. They will also permit a better understanding of abnormal sex differentiation.