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

除了作为细胞外基质的重要组成部分介导结构和机械稳定性外，胶原还参与细胞的粘附、迁移和存活过程。因此，胶原蛋白的功能范围很广。无处不在表达的胶原VI （COLVI）具有由三条COLVI链alpha1、alpha2和alpha3或alpha4、alpha5或alpha6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 myopathy （BM）。由于COLVI在这些疾病中的致病作用，目前发表的关于COLVI分子功能的研究主要集中在骨骼肌。然而，最近的研究结果表明，COLVI也参与与其他器官系统（如中枢神经系统）完整性相关的分子过程。通过自己的初步研究，在疑似aicardii - gouti<e:1>综合征（AGS）的近亲家族中，可以证明COL6A1和COL6A2两种胶原蛋白在RNA和蛋白质水平上完全缺乏。该项目的目的是确定因果突变，并在此背景下，研究这些COLVI胶原链缺乏对这种新型胶原病发病机制的影响。鉴定COLVI调节元件新突变的重要性也与AGS或肌病临床症状患者的鉴别诊断有关，这些患者在已知基因突变检测中呈阴性。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病理机制是开发新的病因治疗方法的先决条件。

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.