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

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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.