C1S — Periodontal Ehlers-Danlos Syndrome

Periodontal Ehlers-Danlos syndrome (pEDS) is a rare autosomal dominant connective tissue disorder characterized by early-onset severe periodontitis, lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, joint hypermobility, and easy bruising (PMID:27745832). pEDS results from heterozygous pathogenic variants in complement subcomponent genes C1R and C1S, implicating complement pathway dysregulation in connective tissue homeostasis.

Genetic evidence for C1S involvement includes two independent families (n=2) with heterozygous missense or in-frame C1S variants in a cohort of 19 families (107 individuals) studied by an international consortium (PMID:27745832), and three additional unrelated probands described in a case series of 13 novel patients (PMID:33890303). Together, this yields five unrelated C1S‐affected probands with segregation of variants in affected relatives.

Inheritance is autosomal dominant with observed segregation in multiple affected family members. Affected relatives total at least five across these pedigrees, confirming co-segregation of C1S variants with pEDS features.

The C1S variant spectrum comprises primarily missense and small in-frame indels affecting inter-domain hinges or subunit interfaces. Notable examples include c.880T>C (p.Cys294Arg) and c.962G>C (p.Cys321Ser), both disrupting CCP modules critical for C1s stability (PMID:27745832; PMID:33890303). No recurrent or founder C1S alleles have been reported to date.

Functional assays demonstrate that pEDS-associated C1S variants evade normal physiological control: overexpressed mutants fail to assemble into C1, generate a truncated 40 kDa Fg40 fragment, and retain protease activity, leading to constitutive extracellular activation of C1s and downstream C4 cleavage (PMID:31921203; PMID:31749804). Patient fibroblasts corroborate decreased secretion of full-length C1s and increased complement cascade activation in the absence of microbial triggers.

Mechanistically, heterozygous C1S variants induce a gain-of-function through aberrant intracellular activation and extracellular presence of active C1s, independent of C1r or C1q assembly, underpinning the connective tissue and periodontal manifestations in pEDS.

No conflicting reports dispute the C1S–pEDS association. Despite the modest number of C1S cases relative to C1R, concordant genetic and functional data support a robust gene–disease link. Additional deep-intronic or structural variants may exist but exceed current evidence caps.

Key Take-home: Heterozygous C1S missense and in-frame variants cause periodontal Ehlers-Danlos syndrome via gain-of-function complement activation, guiding molecular diagnosis and potential targeted complement inhibition strategies.

References

• American journal of human genetics • 2016 • Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement PMID:27745832
• Clinical genetics • 2021 • Periodontal (formerly type VIII) Ehlers-Danlos syndrome: Description of 13 novel cases and expansion of the clinical phenotype PMID:33890303
• Frontiers in immunology • 2019 • Two Different Missense C1S Mutations, Associated to Periodontal Ehlers-Danlos Syndrome, Lead to Identical Molecular Outcomes PMID:31921203
• Frontiers in immunology • 2019 • C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers-Danlos Syndrome PMID:31749804

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