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

Assessment of complement cleavage in gingival fluid during experimental gingivitis in man.

The cleavage of complement may be an important immunopathologic mechanism in the development of gingival inflammation. Utilizing the experimental gingivitis model, cleavage of C3, C4 and B was assessed in gingival fluid following abstention from oral hygiene. 4 male dental students performed stringent oral hygiene measures until the gingival index approached 0, then refrained from any oral hygiene for 21 days. Gingival fluid, sampled with filter paper strips from the mesial surface of all maxillary premolars at 0, 7, 14, and 21 days, was assayed for C3, C4 and B cleavage by multilayer crossed-immunoelectrophoresis. Clinical indices were assessed following gingival fluid sampling. The subjects, who were plaque-free (PI = 0) at the beginning of the study, showed significant plaque accumulation at day 21 (87% of sites with PI greater than or equal to 2). Approximately 90% of the sites were free from clinical inflammation (GI = 0) at the start, but gingivitis increased with time such that 25% of the sites had GI scores of 2 at day 21. Bleeding on probing to the base of the pocket was not observed at day 0, but was observed at 62% of sites by day 21. Statistical analyses showed that all 3 indices significantly increased with time. The %C3 cleavage increased from a mean of 24% at day 0, to 35%, 45% and then 57% at days 7, 14 and 21, respectively, and both days 14 and 21 demonstrated significantly greater C3 conversion than that seen at day 0. The Spearman rank-order correlation coefficient for %C3 conversion versus time was p = 0.52, significant at the p less than 0.0001 level.(ABSTRACT TRUNCATED AT 250 WORDS)link_to_subscribed_fulltex

Assessment of complement cleavage in gingival fluid during experimental gingivitis in man

The cleavage of complement may be an important immunopathologic mechanism in the development of gingival inflammation. Utilizing the experimental gingivitis model, cleavage of C3, C4 and B was assessed in gingival fluid following abstention from oral hygiene. 4 male dental students performed stringent oral hygiene measures until the gingival index approached 0, then refrained from any oral hygiene for 21 days. Gingival fluid, sampled with filter paper strips from the mesial surface of all maxillary premolars at 0, 7, 14, and 21 days, was assayed for C3, C4 and B cleavage by multilayer crossed-immunoelectrophoresis. Clinical indices were assessed following gingival fluid sampling. The subjects, who were plaque-free (PI = 0) at the beginning of the study, showed significant plaque accumulation at day 21 (87% of sites with PI greater than or equal to 2). Approximately 90% of the sites were free from clinical inflammation (GI = 0) at the start, but gingivitis increased with time such that 25% of the sites had GI scores of 2 at day 21. Bleeding on probing to the base of the pocket was not observed at day 0, but was observed at 62% of sites by day 21. Statistical analyses showed that all 3 indices significantly increased with time. The %C3 cleavage increased from a mean of 24% at day 0, to 35%, 45% and then 57% at days 7, 14 and 21, respectively, and both days 14 and 21 demonstrated significantly greater C3 conversion than that seen at day 0. The Spearman rank-order correlation coefficient for %C3 conversion versus time was p = 0.52, significant at the p less than 0.0001 level.(ABSTRACT TRUNCATED AT 250 WORDS)link_to_subscribed_fulltex