MOLECULAR ANALYSIS OF LANGER-GIEDION SYNDROME

Langer-Giedio 综合征的分子分析

• 批准号: 2200799
• 负责人: DAN E WELLS
• 金额: $ 13.76万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2200799
• 关键词: achondroplasia; chromosome aberrations; chromosome deletion; congenital skeletal disorder; cytogenetics; developmental genetics; family genetics; gene expression; gene mutation; gene rearrangement; genetic mapping; genetic polymorphism; genetic recombination; human genetic material tag; human tissue; hybrid cells; in situ hybridization; linkage mapping; northern blottings; nucleic acid sequence; phenotype; pulsed field gel electrophoresis; southern blotting; achondroplasia; chromosome aberrations; chromosome deletion; congenital skeletal disorder; cytogenetics; developmental genetics; family genetics; gene expression; gene mutation; gene rearrangement; genetic mapping; genetic polymorphism; genetic recombination; human genetic material tag; human tissue; hybrid cells; in situ hybridization; linkage mapping; northern blottings; nucleic acid sequence; phenotype; pulsed field gel electrophoresis; southern blotting

The long term objective of this proposal is the characterization at the molecular level of the causes of the developmental defects associated with Langer-Giedion syndrome and the related syndromes trichorhinophalangeal syndrome type I (TRPS-I) and hereditary multiple exostoses. These three dysmorphology syndromes most probably represent different phenotypic expressions of a single "contiguous gene syndrome" resulting from lesions in a region near the distal end of the long arm of human chromosome 8. Langer-Giedion syndrome results from chromosomal deletions or other rearrangements affecting both the gene responsible for the dysmorphic features of TRPS-I and the gene responsible for producing exostoses. The specific aims of this proposal are directed at identifying and characterizing the genes from this region. To this end, cell lines, including somatic cell hybrids, will be established from patients with Langer-Giedion syndrome and TRPS-I. The endpoints of the deletions and rearrangements of patients' chromosomes will be mapped at high resolution on an overlapping clone map of the Langer-Giedion region. This will help to narrow down the critical segment of the chromosome responsible for these syndromes. Linkage analysis of families segregating the TRPS-I and exostoses genes will be used to map the locations of recombination events that may further narrow the regions containing these genes. Expressed sequences within the regions identified by these methods will be identified by screening cDNA libraries, hybridizing genomic clones to Northern blots, searching for evolutionarily conserved sequences, and screening for functional splice sites which mark the boundaries of exons. The genes identified in this way will be characterized at the nucleotide sequence level, and their possible roles in the etiology of Langer-Giedion syndrome will be explored by screening for mutations in patients. The information obtained in this study will increase our understanding of normal developmental processes as well as the disease process, and is likely to lead to improved treatments for patients affected with these syndromes.

该提议的长期目标是在 与之相关的发育缺陷原因的分子水平 Langer-Giedion综合征和相关综合征Trichorhinophalangeal 综合征I型（TRPS-I）和遗传多个遗体。这三个 畸形综合征最有可能代表不同的表型 病变引起的单个“连续基因综合征”的表达 在人类8号染色体的长臂远端附近的区域中。 Langer-Giedion综合征由染色体缺失或其他 重排影响负责畸形的基因 TRP-I的特征和负责产生外遗体的基因。这 该提案的具体目的旨在识别和 表征来自该地区的基因。为此，细胞线， 包括体细胞杂种，将从患者中建立 Langer-Giedion综合征和TRPS-I。删除的终点和 患者染色体的重排将以高分辨率映射 在Langer-Giedion区域的重叠克隆地图上。这将有所帮助 缩小负责染色体的关键部分 这些综合征。分离trps-i和的家庭的连锁分析 外卵形基因将用于绘制重组事件的位置 这可能会进一步缩小包含这些基因的区域。表达 这些方法确定的区域内的序列将是 通过筛选cDNA文库确定，将基因组克隆杂交 北印迹，寻找进化保守的序列，以及 筛选标记外显子边界的功能剪接位点。 以这种方式识别的基因将在核苷酸上进行表征 序列水平及其在Langer-Giedion病因中的可能作用 通过筛查患者突变，将探索综合征。这 在这项研究中获得的信息将增加我们对 正常发育过程以及疾病过程， 可能会改善对受影响的患者的治疗 综合征。