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

Ines Kapferer-Seebacher, Irene Heiss-Kisielewsky, Melanie Pepin, Michael Dorschner, Christopher J. Hale, David Hanna, Margaret Yang, Peter H. Byers, Roland Werner, Albert Amberger, Anna Schossig, Robert Gruber, Hans Christian Hennies, Johannes Zschocke, Timothy J. Aitman, Ann Nordgren, Erik Björck, Anna Lindstrand, Fulya Taylan, Heribert StoiberNicole Thielens, Christine Gaboriaud, Nikolaus Romani, Matthias Schmuth, Cecilia Giunta, Marianne Rohrbach, Michael Bamshad, Christina Chen, Deborah A. Nickerson, David Chitayat, Rachel Silver, Marcus Schmitt-Egenolf, Pernilla Lundberg, Anna L. Mitchell, Eyal Reinstein, Anthony Vandersteen, Jana Vandrovcova, Ruwan Weerakkody, F. Michael Pope, Kirk Aleck, Zoltan Banki, Joszef Dudas, Herbert Dumfahrt, Hady Haririan, James K. Hartsfield, Charles N. Kagen, Uschi Lindert, Thomas Meitinger, Wilfried Posch, Christian Pritz, David Ross, Richard J. Schroer, Georg Wick, Robert Wildin, Doris Wilflingseder

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


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.

Original languageEnglish
Pages (from-to)1005-1014
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number5
StatePublished - Nov 3 2016

Bibliographical note

Publisher Copyright:
© 2016 The Authors

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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