Genetic and Molecular Basis of Congenital Contractures

本研究的目的是探讨先天性挛缩的病因和发病机制。这将通过表征编码快缩肌纤维的肌节蛋白的基因在何种程度上导致统称为远端arthrogriposes（DA）的一组综合征中的挛缩来实现。每一个DA综合征，其中有十个（即，DA 1-DA 10），以手、髋和脚的显性遗传性非进行性挛缩为代表（例如，马蹄内翻足）--最常受孤立性挛缩影响的身体部位。DA的两种最常见形式DA 1和DA 2B分别由TPM 2和TNNI 2或TNNT 3中的突变引起，其中每种突变编码快缩肌纤维的肌钙蛋白-原肌球蛋白复合物的组分。因此，DA综合征是一种新的和独特的一类肌肉疾病所造成的先天性扰动的快速收缩装置。利用118个家族和大约400例DA病例，包括几个大的多重家系，我们建议：（1）进行全基因组筛选，以确定额外的先天性挛缩的位置候选基因;（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）表征具有编码肌节蛋白的基因突变的个体的肌肉的大体、组织学和超微结构特征;（4）研究致病突变、mRNA表达、蛋白表达和DA个体的表型特征。本文产生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）设计突变蛋白质收缩性的体外研究，（3）计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，（5）测试导致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.