C1R – Periodontal Ehlers-Danlos syndrome

This summary reviews the association of C1R with periodontal Ehlers-Danlos syndrome, a rare connective tissue disorder characterized by severe periodontitis, gingival bleeding, and premature loss of teeth. The clinical phenotype includes marked oral manifestations such as gingival bleeding (PMID:30025171) and periodontitis, which are critical for diagnostic decision‑making and patient management.

The disorder follows an autosomal dominant inheritance pattern. Several independent familial studies have demonstrated co‑segregation of heterozygous C1R mutations with the disease phenotype. For example, in one case report a Chinese family exhibited multiple affected members carrying a missense mutation, supporting robust segregation data (PMID:30025171).

Genetic evidence includes the identification of distinct heterozygous missense mutations, with one notable variant being c.265T>C (p.Cys89Arg). This variant was found to co‑segregate with the disease in affected family members. Additional case reports confirm recurrence of pathogenic variants in C1R in multiple families, reinforcing its role in disease pathogenesis (PMID:35365885).

Multi‑patient studies have expanded the evidence base by recruiting 19 independent families comprising over 100 affected individuals. In these cohorts, C1R mutations were consistently associated with the pEDS phenotype, underscoring the genetic heterogeneity and the penetrance of the pathogenic alleles (PMID:27745832).

Functional assessments have provided insights into the mechanism of pathogenicity. In vitro experiments demonstrate that C1R mutants exhibit abnormal protein processing and secretion leading to constitutive activation of the complement pathway. Such data indicate that altered C1r function contributes to the connective tissue abnormalities observed in periodontal Ehlers-Danlos syndrome (PMID:9916740; PMID:31749804).

In conclusion, the integrated genetic and experimental data offer strong evidence that heterozygous mutations in C1R are causative for periodontal Ehlers-Danlos syndrome. The reproducible segregation patterns, multi‑family reports and functional studies collectively support the clinical utility of genetic testing for C1R in patients suspected of pEDS. Key take‑home: Recognition of C1R mutations is essential for timely diagnosis and personalized management of periodontal Ehlers-Danlos syndrome.

References

• Journal of clinical periodontology • 2018 • A Chinese family with periodontal Ehlers‑Danlos syndrome associated with missense mutation in C1R gene PMID:30025171
• 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
• Frontiers in immunology • 2019 • C1R Mutations Trigger Constitutive Complement 1 Activation in Periodontal Ehlers‑Danlos Syndrome PMID:31749804
• Journal of immunology (Baltimore, Md. : 1950) • 1999 • One active C1r subunit is sufficient for the activity of the complement C1 complex: stabilization of C1r in the zymogen form by point mutations PMID:9916740

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