GENETIC CONTROL OF HUMAN GONADAL DIFFERENTIATION

Y染色体在男性初级性别决定中的重要作用 是公认的，触发这一过程的基因被称为 睾丸决定因子(TDF)。对人类TDF基因座的研究有 是由两个条件的存在促成的，46，xy完全 性腺发育不全(患有青光眼的患者缺乏睾丸分化 男性核型)和46，XX男性(受试者睾丸发育 具有明显的女性核型)。TDF基因已被映射到 Y染色体短臂的远端区域。候选基因 因为TDF是古德费罗和他的同事从这个基因座克隆出来的， 被称为性别决定区域Y(SRY)。几行 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蛋白可能通过以下途径影响基因转录 结合到序列特定的位点并通过改变其构象 DNA因此，SRY很可能通过以下方式触发睾丸测定 结合到序列特定的DNA位点。然而，生理上的束缚 人类基因组中的SRY位点(S)和SRY的作用方式 未知。我们的主要假设是SRY基因产物控制 通过启动一系列基因的激活来决定男性的性别。 这项建议的具体目标是：1)确定具体的SRY 人类基因组中的结合位点；2)确定SRY的影响 关于DNA的构象和转录激活；3) 确定自然发生的SRY基因突变的影响 SRY蛋白与其特异性结合能力的研究 网站。4)进一步探讨46，XY性腺的遗传基础 通过研究SRY突变在其他受试者中的发育不全 通过对受影响的个体和与 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 正常睾丸所需基因的复杂相互作用 决心。它们还将允许更好地理解异常 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.