title: Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.
abstract: 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.
authors.affiliation: Department of Operative and Restorative Dentistry, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Ines
authors.initials: I
authors.lastname: Kapferer-Seebacher
authors.affiliation: Department of Pathology, Collagen Diagnostic Laboratory, University of Washington, Seattle, WA 98195-7655, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Pepin
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Roland
authors.initials: R
authors.lastname: Werner
authors.affiliation: MRC Clinical Sciences Centre and Department of Medicine, Imperial College London, London W12 0NN, UK; Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
authors.affiliation: Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institute, Stockholm 171 76, Sweden; Department of Clinical Genetics, Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
authors.affiliation: Division of Virology, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Heribert
authors.initials: H
authors.lastname: Stoiber
authors.affiliation: Institut de Biologie Structurale (IBS), University Grenoble-Alpes, CEA, CNRS, Grenoble 38044, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Thielens
authors.affiliation: Institut de Biologie Structurale (IBS), University Grenoble-Alpes, CEA, CNRS, Grenoble 38044, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Gaboriaud
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Albert
authors.initials: A
authors.lastname: Amberger
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Schossig
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria; Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Gruber
authors.affiliation: Connective Tissue Unit, Division of Metabolism and Children's Research Centre (CRC), University Children's Hospital, Zurich 8032, Switzerland.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195-6320, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195-5065, USA; Center for Mendelian Genomics, University of Washington, Seattle, WA 98195, USA; Seattle Children's Research Institute, Seattle, WA 98195-7655, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bamshad
authors.affiliation: Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institute, Stockholm 171 76, Sweden; Department of Clinical Genetics, Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Björck
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195-5065, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Chen
authors.affiliation: The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.affiliation: Department of Pathology, Collagen Diagnostic Laboratory, University of Washington, Seattle, WA 98195-7655, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Dorschner
authors.affiliation: Department of Public Health and Clinical Medicine, Dermatology, Umeå University, Umeå 901 87, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmitt-Egenolf
authors.affiliation: Department of Pathology, Collagen Diagnostic Laboratory, University of Washington, Seattle, WA 98195-7655, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hale
authors.affiliation: Department of Pathology, Collagen Diagnostic Laboratory, University of Washington, Seattle, WA 98195-7655, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hanna
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria; Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck 6020, Austria; Cologne Center for Genomics, University of Cologne, Cologne 50931, Germany; Department of Biological Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Hennies
authors.affiliation: Department of Operative and Restorative Dentistry, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Irene
authors.initials: I
authors.lastname: Heiss-Kisielewsky
authors.affiliation: Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institute, Stockholm 171 76, Sweden; Department of Clinical Genetics, Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Lindstrand
authors.affiliation: Department of Molecular Periodontology, Umeå University, Umeå 901 87, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Lundberg
authors.affiliation: Departments of Genetics and Genome Sciences and Pediatrics, Case Western Reserve University Medical Center, Cleveland, OH 44106, USA.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Mitchell
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195-5065, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Medical Genetics Institute, Meir Medical Center, Kfar Saba 44100, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Reinstein
authors.affiliation: Connective Tissue Unit, Division of Metabolism and Children's Research Centre (CRC), University Children's Hospital, Zurich 8032, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Rohrbach
authors.affiliation: Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Romani
authors.affiliation: Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmuth
authors.affiliation: The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: Rachel
authors.initials: R
authors.lastname: Silver
authors.affiliation: Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institute, Stockholm 171 76, Sweden.
authors.forename: Fulya
authors.initials: F
authors.lastname: Taylan
authors.affiliation: Maritime Medical Genetics Service, IWK Health Centre, Halifax, NS B3K 6R8, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Vandersteen
authors.affiliation: King's College London, Department of Medical & Molecular Genetics, Guy's Hospital, London WC2R 2LS, UK.
authors.forename: Jana
authors.initials: J
authors.lastname: Vandrovcova
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Ruwan
authors.initials: R
authors.lastname: Weerakkody
authors.affiliation: Department of Pathology, Collagen Diagnostic Laboratory, University of Washington, Seattle, WA 98195-7655, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Yang
authors.affiliation: West Middlesex University Hospital, Isleworth, Middlesex TW7 6AF, UK; Hospital of St John & St Elizabeth, London NW8 9NH, UK.
authors.forename: F Michael
authors.initials: FM
authors.lastname: Pope
authors.affiliation: Department of Pathology, Collagen Diagnostic Laboratory, University of Washington, Seattle, WA 98195-7655, USA; Department of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195, USA. Electronic address: pbyers@u.washington.edu.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Byers
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria. Electronic address: johannes.zschocke@i-med.ac.at.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D015923:Complement C1r / Q000235:genetics*; D003173:Complement C1s / Q000235:genetics*; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D059472:Exome; D005260:Female; D017353:Gene Deletion; D056426:Genetic Loci; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010518:Periodontitis / Q000175:diagnosis / Q000235:genetics*; D011487:Protein Conformation; D055815:Young Adult
chemical_list: D015923:Complement C1r; D003173:Complement C1s