Investigations of cause and effects of the deficiency of collagens COL6A1 and COL6A2.

胶原蛋白除了作为细胞外基质的重要组成部分调节结构和机械稳定性外，还参与细胞的黏附、迁移和存活过程。因此，胶原蛋白的功能涉及广泛的光谱。普遍表达的胶原蛋白VI(Colvi)具有分别由Alpha1、Alpha2和Alpha3或Alpha4、Alpha5或Alpha6三个Colvi链组成的超分子结构。Colvi编码基因COL6A1、COL6A2和COL6A3的突变是所谓Colvi肌病的原因，临床上主要表现为先天性肌营养不良型Ullrich(UCMD)和Bethlem肌病(BM)。由于其在这些疾病中的致病作用，迄今为止发表的关于COLVI分子功能的研究主要集中在骨骼肌。然而，最近的发现表明，Colvi也参与了与其他器官系统(如中枢神经系统)的完整性相关的分子过程。根据自己的初步研究，在一个疑似Aicardi-Gtières综合征(AGS)的血缘家庭中，COL6A1和COL6A2两种胶原蛋白在RNA和蛋白质水平上可能完全缺乏。本项目的目的是确定原因突变，并在此背景下，调查这些Colvi胶原链的缺陷在这种新的胶原病发病机制中的作用。对于有AGS或肌病临床症状的患者的鉴别诊断，识别Colvi调节元件中的新突变的重要性也是相关的，这些患者的已知基因突变检测为阴性。目前，AGS以及BM和UCMD只能对症治疗。更好地了解这些疾病的基本发病机制是开发新的病因疗法的前提。

Besides their role as an essential component of the extracellular matrix mediating structural and mechanical stability, collagens are also involved in processes of adhesion, migration and the survival of cells. Thus, the functions of the collagens extend over a broad spectrum.The ubiquitously expressed collagen VI (COLVI) has a supramolecular structure composed of the three COLVI chains alpha1, alpha2 and alpha3 or alpha4, alpha5 or alpha6, respectively. Mutations in the COLVI-coding genes COL6A1, COL6A2 and COL6A3 are the cause of the so-called COLVI myopathies, which appear clinically mainly as congenital muscular dystrophy type Ullrich (UCMD) and as Bethlem myopathy (BM). Due to its causal role for these diseases, the studies published so far on the molecular functions of COLVI mainly focus on skeletal muscle. However, recent findings indicate that COLVI is also involved in molecular processes relevant to the integrity of other organ systems such as the central nervous system. By own preliminary studies, a complete deficiency of the two collagens COL6A1 and COL6A2 at the RNA and protein level could be demonstrated in a consanguineous family with suspected Aicardi-Goutières syndrome (AGS). The aim of this project is to identify the causal mutation and, in this context, to investigate the effects of the deficiency of these COLVI collagen chains for the pathogenesis of this novel collagenopathy. The importance of the identification of a new mutation in a COLVI regulating element is also relevant with regard to the differential diagnosis of patients with clinical signs of AGS or myopathy, who tested negative for mutations in known genes. Currently, AGS as well as BM and UCMD can only be treated symptomatically. A better understanding of the basic pathomechanisms of these diseases is the prerequisite for the development of new causaltherapies.