Genetic and Molecular Basis of Congenital Contractures

本研究的目的是探讨先天性挛缩的病因及发病机制。这将通过描述编码快速抽搐肌纤维的肌合成蛋白的基因在多大程度上导致一组综合征（统称为远端关节挛缩（DAs））的挛缩来完成。每种DA综合征共有10种（即DA1-DA10），其典型特征主要是遗传性的手、髋和足（如内翻足）的非进行性挛缩，这些部位最常受孤立性挛缩的影响。两种最常见的DA， DA1和DA2B，分别是由TPM2和TNNI2或TNNT3突变引起的，它们分别编码快速收缩肌纤维肌钙蛋白-原肌球蛋白复合物的一种成分。因此，DA综合征是一种新的、独特的肌肉疾病，由先天性的快速抽搐收缩器官的扰动引起。利用118个家族和大约400例DA病例，包括几个大的、多重的家系，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病例中编码候选肉瘤蛋白的位置候选基因和功能候选基因的突变；(3)描述编码肌合成蛋白基因突变个体肌肉的大体、组织学和超微结构特征；(4)探讨DA患者致病突变、mRNA表达、蛋白表达与表型特征之间的关系。本文产生的数据将为我们提供一个机会：(1)直接研究先天性挛缩的发病机制，(2)用突变蛋白设计体外收缩性研究，(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，以及(5)测试导致DA综合征的基因是否与特发性内翻足易感性相关。

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.