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

研究胶原蛋白 COL6A1 和 COL6A2 缺乏的原因和影响。

• 批准号: 404979920
• 负责人: Dr. Nadja Lucas
• 金额: --
• 依托单位: Klinik und Poliklinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/404979920?language=en
• 关键词: Investigations; cause; effects; deficiency; collagens

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.

除了作为介导结构和机械稳定性的细胞外基质的基本组分的作用之外，胶原还参与细胞的粘附、迁移和存活过程。普遍表达的胶原VI（COLVI）具有分别由三条COLVI链α 1、α 2和α 3或α 4、α 5或α 6组成的超分子结构。COLVI编码基因COL 6A 1、COL 6A 2和COL 6A 3中的突变是所谓的COLVI肌病的原因，其在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因果作用，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上。然而，最近的研究结果表明，COLVI也参与了与其他器官系统（如中枢神经系统）完整性相关的分子过程。本文报道一个疑似Aicardi-Goutières综合征（AGS）的家系，在RNA和蛋白质水平上均发现两种胶原蛋白COL 6A 1和COL 6A 2的完全缺失。该项目的目的是确定因果突变，并在此背景下，调查这些COLVI胶原蛋白链的缺陷对这种新型胶原蛋白病发病机制的影响。鉴定COLVI调节元件中的新突变的重要性也与具有AGS或肌病临床体征的患者的鉴别诊断相关，这些患者在已知基因中的突变检测为阴性。目前，AGS以及BM和UCMD只能通过手术治疗。更好地理解这些疾病的基本病理机制是开发新的钙拮抗剂疗法的先决条件。