GENETIC CONTROL OF HUMAN GONADAL DIFFERENTIATION

人类性腺分化的遗传控制

• 批准号: 3329910
• 负责人: GARY DAVID BERKOVITZ
• 金额: $ 16.55万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-06-01 至 1996-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3329910
• 关键词: DNA binding protein; DNA footprinting; RNase protection assay; Turner's syndrome; chemical binding; chimeric proteins; conformation; family genetics; gel mobility shift assay; gene expression; gene mutation; genetic promoter element; genetic transcription; genome; hermaphroditism; human genetic material tag; human subject; linkage mapping; male; methylation; nucleic acid sequence; oligonucleotides; polymerase chain reaction; reporter genes; sex chromosomes; sex determination; sex linked trait; testis; transfection /expression vector

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.

Y染色体在原发性男性确定中的重要作用 已经建立得很好，触发此过程的基因称为 睾丸确定因子（TDF）。 人类中TDF基因座的研究 存在两个条件，即46，XY完整，从而促进了 性腺发育不全（患有A的受试者缺乏睾丸分化 雄性核型）和46，XX男性（受试者睾丸的发展 具有明显的雌性核型）。 TDF基因座已映射到 Y染色体短臂的远端区域。 候选基因 因为TDF是由Goodfellow和同事从这个位置克隆的，并且 被称为性别确定的区域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组（HMG）。 最近的研究表明，HMG蛋白可能会影响基因转录 与序列特定位点结合，并通过改变 脱氧核糖核酸。 因此，很可能通过 与序列特异性DNA位点结合。 但是，生理结合 人类基因组中SRY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 通过激活级联基因的激活来确定男性性别。 该提案的具体目的是：1）确定特定的SRY 人类基因组中的结合位点； 2）确定SRY的影响 关于DNA和转录激活的构象； 3）到 确定自然发生的突变在SRY基因中的影响 关于SRY蛋白与其特定结合相互作用的能力 站点。 4）进一步研究46，XY性腺的遗传基础 通过研究SRY突变的其他受试者的失去障碍 受影响的个体并通过与亲属进行联系分析 性腺发育不全的遗传形式。 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的复杂相互作用 决心。 他们还将更好地理解异常 性别差异。