MOLECULAR ANALYSIS OF LANGER-GIEDION SYNDROME

Langer-Giedio 综合征的分子分析

• 批准号: 3329601
• 负责人: DAN E WELLS
• 金额: $ 13.23万
• 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/3329601
• 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

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.

本提案的长期目标是在 分子水平的原因的发展缺陷相关的 Langer-Giedion综合征及其相关综合征 综合征I型（TRPS-I）和遗传性多发性外生骨疣。这三 畸形综合征最可能代表不同的表型 由病变引起的单个“邻接基因综合征”的表达 位于人类8号染色体长臂末端附近的区域。 Langer-Giedion综合征由染色体缺失或其他 基因重排既影响了导致畸形的基因， TRPS-I和负责产生外生骨疣的基因的特征。的 本建议的具体目标是确定和 来描述这个区域的基因。为此，细胞系， 包括体细胞杂交，将从患有 Langer-Giedion综合征和TRPS-I。删除的端点和 患者染色体的重排将以高分辨率绘制 在朗格-吉迪翁地区的重叠克隆地图上这将有助于 来缩小染色体的关键片段， 这些症状。分离TRPS-I和TRPS-II的家系的连锁分析 外生骨疣基因将被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。表示 通过这些方法鉴定的区域内的序列将被 通过筛选cDNA文库，将基因组克隆与 北方印迹，寻找进化保守序列， 筛选标记外显子边界的功能性剪接位点。 以这种方式鉴定的基因将在核苷酸上进行表征。 序列水平，以及它们在Langer-Giedion病因学中的可能作用 将通过筛查患者的突变来探索综合征。的 本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， 可能会导致改善患者的治疗受这些 综合征