Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

Women with Ehlers-Danlos syndrome experience low oral health-related quality of life.

AIMS: To investigate the perceived impact of oral health-related quality of life problems in individuals with Ehlers-Danlos syndrome. METHODS: Members of the Swedish Ehlers-Danlos Syndrome Association completed the Oral Health Impact Profile (OHIP-14). Of the 250 participating individuals, 223 were women, and they were the main focus of the analyses. The results were compared with a previous study of the oral health impact on quality of life in the Swedish population. Statistical methods used for comparison were the Student t and chi-square tests. RESULTS: The mean OHIP-14 value for the entire Ehlers-Danlos syndrome group was 11.1. The mean for women was 11.8, which was significantly higher than 6.8 of the comparison group. The OHIP-14 score varied among age groups, and the highest mean value was found in the age group between 56 and 65 years of age. The most statistically significant differences between the subjects with Ehlers-Danlos syndrome and the comparison group were found for OHIP items 3, 4, and 8: "I have had pain in the mouth," "I have had discomfort when eating," and "I have been forced to interrupt meals." CONCLUSION: It is well-known that Ehlers-Danlos syndrome has a considerable impact on health-related quality of life, and this study is the first to reveal that women with Ehlers-Danlos syndrome report a low oral health-related quality of life as measured with the OHIP-14. Dimensions that were particularly relevant were physical pain, psychologic discomfort, and handicap.

C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers-Danlos Syndrome.

Heterozygous missense or in-frame insertion/deletion mutations in complement 1 subunits C1r and C1s cause periodontal Ehlers-Danlos Syndrome (pEDS), a specific EDS subtype characterized by early severe periodontal destruction and connective tissue abnormalities like easy bruising, pretibial haemosiderotic plaques, and joint hypermobility. We report extensive functional studies of 16 C1R variants associated with pEDS by in-vitro overexpression studies in HEK293T cells followed by western blot, size exclusion chromatography and surface plasmon resonance analyses. Patient-derived skin fibroblasts were analyzed by western blot and Enzyme-linked Immunosorbent Assay (ELISA). Overexpression of C1R variants in HEK293T cells revealed that none of the pEDS variants was integrated into the C1 complex but cause extracellular presence of catalytic C1r/C1s activities. Variants showed domain-specific abnormalities of intracellular processing and secretion with preservation of serine protease function in the supernatant. In contrast to C1r wild type, and with the exception of a C1R missense variant disabling a C1q binding site, pEDS variants had different impact on the cell: retention of C1r fragments inside the cell, secretion of aggregates, or a new C1r cleavage site. Overexpression of C1R variants in HEK293T as well as western blot analyses of patient fibroblasts showed decreased levels of secreted C1r. Importantly, all available patient fibroblasts exhibited activated C1s and activation of externally added C4 in the supernatant while control cell lines secreted proenzyme C1s and showed no increase in C4 activation. The central elements in the pathogenesis of pEDS seem to be the intracellular activation of C1r and/or C1s, and extracellular presence of activated C1s that independently of microbial triggers can activate the classical complement cascade.