GENES, CHROMOSOMAL REGIONS AND DEVELOPMENTAL DISORDERS

基因、染色体区域和发育障碍

• 批准号: 2889217
• 负责人: GAIL A BRUNS
• 金额: $ 23.4万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2889217
• 关键词: Wilms' tumor; congenital eye disorder; frontal lobe /cortex; gene deletion mutation; gene expression; gene rearrangement; genetic disorder; genetic mapping; human genetic material tag; human tissue; immunocytochemistry; in situ hybridization; laboratory mouse; mental retardation; molecular cloning; molecular genetics; motor cortex; neurogenesis; reproductive system disorder; urinary tract disorder

This project is focused on genes, chromosomal regions, rearrangements and developmental disorders. The deletion region of the WAGR contiguous gene syndrome (Wilms tumor, aniridia, genitourinary anomalies and mental retardation ) is a model for other chromosomal areas associated with complex developmental disorders. In this project, the deletion region (distal 11p12- 11p14.3) was divided into multiple subintervals; a long range restriction and YAC based map anchored at HTF islands, transcribed regions, and 26 rearrangement breakpoints developed; and a number of new genes identified, including Wilms tumor-1. That both the Wilms tumor and aniridia loci defined new DNA binding proteins with important roles in organogenesis provided insight into the nature of genes associated with haplo-insufficiency malformation disorders in man. Little is known, however, of the genes underlying the mental impairment of the syndrome. It is here proposed to study, both as a locus likely to have a fundamental function during brain development and as a candidate for association with part of this phenotypic feature, another new WAGR region gene. This gene encodes a previously unknown~ancient conserved~ sequence - likely a ~class marking~ functional or architectural domain; is prominently and predominantly expressed in fetal, but not adult cortex; is the signal member of a new gene family; and maps within a telomeric deletion interval previously associated with the mental retardation of some WAGR patients. As with other contiguous gene syndromes, WAGR associated deletions are frequently large, encompassing the 11p13 R band with extension into adjacent G bands. The multifaceted map of this region developed here, which crosses 2 G/R band boundaries, provides a framework for investigating the interrelationships of chromosomal domain features, replication, transcription units and rearrangement breakpoint environments. To this end, a replication timing map of distal 11p12-11p14.2 is to be superimposed on and integrated with the WAGR region interval,, gene, HTF island and breakpoint map. The mechanisms of formation of chromosome deletions associated with contiguous genes syndromes are unknown. To determine whether architectural features at WAGR region deletion breakpoints differ depending on the chromosomal domain environments of their initiation and termination points, a number of deletion boundaries will be cloned.

这个项目的重点是基因，染色体区域， 重排和发育障碍。缺失区 WAGR邻近基因综合征(Wilms瘤，无虹膜， 泌尿生殖系统异常和精神发育迟缓)是 与复杂发育相关的其他染色体区域 精神错乱。在本项目中，缺失区域(11p12-末端) 11p14.3)被分成多个子区间；一个大范围 限制和基于YAC的地图停泊在HTF岛屿， 转录区，形成26个重排断裂点； 并发现了一些新的基因，包括Wilms Tumor-1。 Wilms肿瘤和无虹膜基因都定义了新的DNA 提供在器官发生中具有重要作用的结合蛋白 对与单纯性功能不全相关的基因本质的洞察 人类的畸形障碍。然而，人们对此知之甚少 导致该综合征精神损害的基因。它是 这里提出要研究一下，两者都有可能作为一个基因座 在大脑发育过程中的基本功能，并作为候选人 为了与这种表型特征的一部分联系在一起，另一个新的 WAGR区基因。该基因编码一个先前的 未知~古代保守~序列-可能是~类标记~ 功能或建筑领域；是突出的和 主要在胎儿皮质表达，但不在成人皮质中表达；是 一个新基因家族的信号成员；以及端粒内的图谱 先前与精神发育迟滞相关的删除间隔 一些WAGR患者。与其他相邻基因一样 综合征，与WAGR相关的缺失通常很大， 包含11p13R带并延伸到相邻的G 乐队。这个地区的多面性地图就是在这里绘制的， 它跨越了2 G/R频段的界限，为 研究染色体结构域之间的相互关系 特征、复制、转录单位和重排 断点环境。为此，复制时序图 远端11p12-11p14.2要叠加并与之整合 WAGR区间隔、基因、HTF岛和断裂点 地图。染色体缺失的形成机制 与相邻基因相关的综合征尚不清楚。至 确定是否删除WAGR区域的建筑特征 断点因染色体区域的不同而不同 它们的起始点和终止点的环境，一些 的删除边界将被克隆。