Genetic and Molecular Basis of Congenital Contractures

该项目的目标是研究先天性挛缩的病因和发病机制。这将通过表征编码快肌纤维肌节蛋白的基因在统称为远端关节弯曲（DA）的一组综合征中引起挛缩的程度来实现。每种 DA 综合征共有 10 种（即 DA1-DA10），其典型特征是手部、臀部和足部（例如马蹄内翻足）的显性遗传性非进行性挛缩，这些部位是最常受孤立性挛缩影响的身体部位。 DA 的两种最常见形式 DA1 和 DA2B 分别是由 TPM2 和 TNNI2 或 TNNT3 突变引起的，每种突变都编码快肌纤维肌钙蛋白-原肌球蛋白复合物的一个组成部分。因此，DA 综合征是一类新的、独特的肌肉疾病，由快肌收缩器官的先天性紊乱引起。利用 118 个家庭和大约 400 个 DA 病例的集合，包括几个大型、多重谱系，我们建议：(1) 进行全基因组筛选，以确定先天性挛缩的其他位置候选基因； (2) 筛选 DA 病例中编码候选肌节蛋白的位置候选基因和功能候选基因的突变； (3) 表征编码肌节蛋白基因突变的个体肌肉的总体、组织学和超微结构特征； (4) 研究 DA 个体的致病突变、mRNA 表达、蛋白表达和表型特征之间的关系。本文生成的数据将为我们提供机会：(1) 直接研究先天性挛缩的发病机制，(2) 设计突变蛋白收缩性的体外研究，(3) 规划开发先天性挛缩动物模型的策略，(4) 考虑新的治疗干预措施，以及 (5) 测试引起 DA 综合征的基因是否与特发性马蹄内翻足的易感性相关。

The goal of this project is to investigate the etiology and pathogenesis of congenital contractures. This will be accomplished by characterizing the extent to which genes that encode sarcomeric proteins of fast-twitch myofibers cause contractures in a group of syndromes collectively called the distal arthrogryposes (DAs). Each DA syndrome, of which there are ten (i.e., DA1-DA10), is typified by dominantly inherited non-progressive contractures of the, hand, hips, and feet (e.g., clubfoot)--the body areas most commonly affected by isolated contractures. The two most common forms of DA, DA1 and DA2B, are caused by mutations in TPM2 and TNNI2 or TNNT3, respectively, each of which encodes a component of the troponin-tropomyosin complex of fasttwitch myofibers. Thus, DA syndromes are new and a unique class of muscle disease caused by congenital perturbation of the fast-twitch contractile apparatus. Using a collection of 118 families and approximately 400 cases with DA, including several large, multiplex pedigrees, we propose to: (1) perform a genome-wide screen to identify additional positional candidate genes for congenital contractures; (2) screen DA cases for mutations in positional candidate genes and functional candidate genes that encode candidate sarcomeric proteins; (3) characterize the gross, histological, and ultrastructural characteristics of muscles of individuals with mutations in genes that encode sarcomeric proteins; and (4) investigate the relationship between disease-causing mutations, mRNA expression, protein expression, and phenotypic characteristics of individuals with DA. The data generated herein will provide us with an opportunity to (1) directly study the pathogenesis of congenital contractures, (2) design in-vitro studies of contractility with mutant proteins, (3) plan a strategy for developing an animal model of congenital contractures, (4) consider novel therapeutic interventions, and (5) test whether genes that cause DA syndromes are associated with susceptibility to idiopathic clubfoot.