BEALS SYNDROME & ITS RELATIONSHIP TO MARFAN SYNDROME

比尔斯综合症

• 批准号: 2081038
• 负责人: CHERYL L MASLEN
• 金额: $ 11.71万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-15 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2081038
• 关键词: Marfan syndrome; autosomal dominant trait; calcium binding protein; congenital skeletal disorder; epidermal growth factor; epitope mapping; extracellular matrix proteins; gene mutation; genetic techniques; human subject; immunoelectron microscopy; immunofluorescence technique; linkage mapping; monoclonal antibody; nucleic acid sequence; phenotype; protein sequence

Beals syndrome, also known as congenital contractural arachnodactyly (CCA), is an inherited disorder thought to be due to a defect in a connective tissue component. Affected individuals display a Marfanoid habitus, joint contractures, ear deformities and occasional cardiovascular defects. CCA has been presumed to be allelic to the Marfan syndrome (MfS) because of striking phenotypic similarities. However, recent linkage data indicates that a partially characterized gene on chromosome 5 is responsible for CCA rather than the fibrillin gene on chromosome 15 which is defective in MfS. The sequence of the putative CCA gene shows a high degree of identity with the fibrillin gene suggesting that the two proteins are related. However, the CCA gene product has not yet been isolated, nor is anything known about its tissue distribution or physiological function. Furthermore, no mutations have been identified in any CCA patient. The long-term objectives of this study are to determine the pathogenesis of CCA and to clarify its relationship to MfS. This involves defining and comparing the roles of the proteins involved and understanding the consequences of mutations in relationship to the disease phenotypes. The range and nature of mutations giving rise to CCA will be determined in a group of CCA patients using Chemical Mismatch Cleavage analysis. The consequences of those mutations to the structure and function of the defective protein will be determined by comparative analysis of the properties of normal and mutated domains. From a comparison of the deduced amino acid sequence of the CCA gene with fibrillin, dissimilar regions will be selected to make synthetic peptides specific for the CCA gene product. These will be used to prepare antisera and monoclonal antibodies for protein characterization. Immunofluorescent tissue staining and immunoelectron microscopy will reveal the tissue distribution of the epitope and tissue structures that contain the CCA gene product. The antibodies will also be used to isolate the protein from extracts or proteolytic digests of appropriate tissues or from cell culture medium. Limited protein sequence analysis will confirm that the isolated protein is indeed the CCA gene product. The homologous region between fibrillin and the CCA gene product consists largely of repeated epidermal growth factor precursor (pEGF)-like domains containing predicted calcium binding sites and domains that are homologous to a domain in TGF-beta-1 binding protein. Missense mutations in these domains have been identified in several Marfan patients. Phenotypic similarities between the MfS and CCA suggest that similar mutations may be found in CCA. In addition, fibrillin has a potential SH3 binding domain that is not present in the CCA protein. This strongly implicates this region as a site of protein- protein interaction making it an important distinguishing feature between the two proteins. An expression system in E. coli will be designed to synthesize selected structural domains so that the normal physiological function and the effect of CCA mutations can be studies. Elucidating the structural and functional differences between the CCA protein and fibrillin will help explain the comparative pathogenesis of these diseases and the role of the protein in the development of the human cardiovascular, skeletal and ocular systems.

比尔斯综合症，也称为先天性芳基芳香族 （CCA），是一种遗传性疾病，认为是由于 结缔组织成分。 受影响的人表现出marfanoid 习惯，关节染色，耳朵畸形和偶尔 心血管缺陷。 CCA被认为是 Marfan综合征（MFS）是由于惊人的表型相似性。 但是，最近的链接数据表明部分表征 5号染色体上的基因负责CCA，而不是原纤维蛋白 在MFS中有缺陷的15染色体上的基因。 序列 假定的CCA基因与原纤维蛋白基因具有高度的认同 表明这两种蛋白是相关的。 但是，CCA基因 产品尚未孤立，对其组织也不知道 分布或生理功能。 此外，没有突变有 在任何CCA患者中都被发现。 这个长期目标 研究是为了确定CCA的发病机理并阐明其发病机理 与MFS的关系。 这涉及定义和比较 涉及的蛋白质并了解突变的后果 与疾病表型的关系。 的范围和性质 引起CCA的突变将在一组CCA中确定 使用化学不匹配裂解分析的患者。 后果 那些对缺陷蛋白的结构和功能的突变 将通过比较正常特性的比较分析来确定 和突变的域。 从推导氨基酸的比较中 用纤维蛋白，不同区域的CCA基因的序列将是 被选为使CCA基因产物具有特异性的合成肽。 这些将用于制备抗血清和单克隆抗体 蛋白质表征。 免疫荧光组织染色和 免疫电子显微镜将揭示组织分布 包含CCA基因产物的表位和组织结构。 这 抗体也将用于从提取物或 适当组织或细胞培养基的蛋白水解消化。 有限的蛋白质序列分析将确认分离的蛋白 确实是CCA基因产物。 纤维蛋白之间的同源区域 CCA基因产物主要由反复的表皮生长组成 因子前体（PEGF）类似于预测钙结合的结构域 与TGF-BETA-1结合中域同源的站点和域 蛋白质。 这些领域中的错义突变已在 几名马凡患者。 MFS和CCA之间的表型相似性 表明在CCA中可能会发现类似的突变。 此外， 纤维蛋白具有潜在的SH3结合结构域，该结构域不存在 CCA蛋白。 这强烈暗示该区域是蛋白质的位置 蛋白质相互作用使其成为重要的区别特征 两种蛋白质。 大肠杆菌中的表达系统将被设计为 合成选定的结构域，以使正常的生理 功能和CCA突变的影响可能是研究。 阐明 CCA蛋白和功能差异 纤维蛋白将有助于解释这些的比较发病机理 疾病和蛋白质在人类发展中的作用 心血管，骨骼和眼系统。