Ehlers–Danlos syndrome (EDS) periodontal-type (EDS-VIII) is a connective-tissue disorder characterized by aggressive periodontitis and various joint and skin manifestations. It is inherited as an autosomal dominant trait. In 2003, a genetic study on three families established linkage to an interval on chromosome 12p13. Our new and unpublished investigations started with linkage and exome analysis in a large Tyrolean family with this disease and was subsequently extended to a large number of families with EDS periodontal-type. This led to the identification of heterozygous missense mutations in the complement C1R or C1S genes in affected individuals from an additional set of 14 families. Up to now, the proteases C1r and C1s are mainly known to play a role in the activation of the classical complement cascade, a major element of antimicrobial host defense. Individuals with homozygous null mutations in C1R or C1S are highly susceptible to microbial infections and to have greater risk in developing autoimmune diseases like systemic lupus erythematosus. Heterozygous null mutations in C1R / C1S appear to be asymptomatic and there has been no previous reports on a connection of aggressive periodontitis or Ehlers-Danlos syndrome with C1R and C1S mutations. The aim of this project is to clarify both the clinical symptoms as well as the underlying molecular mechanisms of EDS periodontal type in a multidisciplinary approach. Starting with the identification of C1R or C1S mutation in patients, the diagnosis of EDS periodontal type will be complemented by various clinical investigations on oral, joint, and skin features, autoimmunological symptoms as well as vascular disease. The structural etiology of oral soft tissues will be explored by histological and immunochistochemical analyses. Alterations of the protease function in terms of interaction with C1q and activation of the classical pathway of complement will be investigated using recombinant mutant proteins and patient serum. Since C1r and C1s interact with the collagen-like structure of C1q, we will explore the hypotheses of abnormal interaction of mutant C1r and C1s with soluble procollagens as well as possible interference with their processing. The structural impact of mutations will be investigated in relation to the identified functional impact to better characterize the molecular defects. Proving the C1r/C1s mutations as the hub of connective tissue disorders implicates yet unknown functional properties and may result in new ways of understanding crosslinks between inflammatory diseases and connective tissue homeostasis.