C1r and C1s Mutations in Ehlers-Danlos syndrome periodontal

Ehlers-Danlos syndrome (EDS) periodontal-type is a rare connective-tissue disorder characterized by rapid progressive periodontitis and tooth loss in the third decade of life, as well as various joint and skin manifestations. From a patients perspective, the disease has a tremendous influence on quality of life. We have identified a 5-generation Austrian family with EDS periodontal-type which has been clinically and genetically investigated. Genetical invetsigations were carried out or re-examined in 14 additional families with EDS periodontal- type. All affected family members were shown to have mutations in complement 1 (C1), which is an important immunologic complex. Elucidating the exact pathomechanism by which mutations in C1 cause EDS periodontal- type is the aim of the current project. We hypothesize, that the clinical features of EDS periodontal type are linked to both, structural alterations of the connective tissue as well as a disturbance of immunological functions due to mutations in C1. Starting with the idenfication of C1 mutations in 15 families, the diagnosis of EDS periodontal-type will be complemented by various clinical investigations on oral, joint, skin features, autoimmunologic symptoms as well as vascular diseases. Interaction experiments of complement proteins will test the influence of C1 mutations on binding behaviour and functional activity of the C1 complex. Interaction experiments with collagen will test the influence of C1 mutations on connective tissues. Structural etiology of oral soft tissues will be explored by histological and immunochistochemical analyses. In the current classification of EDS, the existence of EDS periodontal-type as an independent entity has been severely questioned. With the present study we (1) prove that EDS periodontal-type is an autonomous entity, (2) provide the genetic and functional basis of the disease, and (3) provide the means for improved diagnosis of this condition. Proving the C1 mutations as the hub of connective tissue disorders implicates yet unknown functional properties and will likely result in radically new ways of understanding crosslinks between inflammatory diseases and connective tissue homeostasis. This link explains the increased prevalence of some multi-system symptoms in EDS periodontal-type, observed in our patients, and may be of relevance to other conditions.

The periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal dominant disorder caused by heterozygous missense or in-frame insertion/deletion mutations in the genes for complement 1 subunits C1r or C1s. Diagnostic criteria include severe periodontal bone loss with early onset as well as connective tissue fragility manifested by joint hypermobility, thin and hyperextensible skin, abnormal scarring and poor wound healing. In addition, two major diagnostic criteria, with high prevalence in pEDS patients, are lack of attached gingiva and pretibial discolorations. The functional and structural impact of 16 C1R and two C1S mutations known at the onset of the study were investigated. Our results showed that hallmarks of pEDS include uncontrolled activation and cleavage of C1s, inability to form the C1 complex and intracellular accumulation of mutated protein fragments at least for some mutations. We hypothesize that a combination of intracellular and extracellular effects contribute to the pathogenesis of pEDS. Additional clinical investigations showed that pEDS is associated with adult-onset progressive leukoencephalopathy and dental implants are contraindicated because they trigger a rapid progressing peri-implant bone loss in individuals with pEDS. The study unravelled the parts of the pathogenetic mechanism of pEDS. Further studies are needed to obtain clear insights in non-canonical functions of complement components especially in association with connective tissue homeostasis. Resolving the full pathomechanism of pEDS may help to understand other Ehlers-Danlos syndrome types and other connective tissue disorders.