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Am J Hum Genet. 2016 Nov 3;99(5):1005-1014. doi: 10.1016/j.ajhg.2016.08.019. Epub 2016 Oct 13.

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

Author information

1
Department of Operative and Restorative Dentistry, Medical University of Innsbruck, Innsbruck 6020, Austria.
2
Department of Pathology, Collagen Diagnostic Laboratory, University of Washington, Seattle, WA 98195-7655, USA.
3
Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria.
4
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.
5
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.
6
Division of Virology, Medical University of Innsbruck, Innsbruck 6020, Austria.
7
Institut de Biologie Structurale (IBS), University Grenoble-Alpes, CEA, CNRS, Grenoble 38044, France.
8
Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria; Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck 6020, Austria.
9
Connective Tissue Unit, Division of Metabolism and Children's Research Centre (CRC), University Children's Hospital, Zurich 8032, Switzerland.
10
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.
11
Department of Genome Sciences, University of Washington, Seattle, WA 98195-5065, USA.
12
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.
13
Department of Public Health and Clinical Medicine, Dermatology, Umeå University, Umeå 901 87, Sweden.
14
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.
15
Department of Molecular Periodontology, Umeå University, Umeå 901 87, Sweden.
16
Departments of Genetics and Genome Sciences and Pediatrics, Case Western Reserve University Medical Center, Cleveland, OH 44106, USA.
17
Medical Genetics Institute, Meir Medical Center, Kfar Saba 44100, Israel.
18
Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck 6020, Austria.
19
Department of Molecular Medicine and Surgery and Centre for Molecular Medicine, Karolinska Institute, Stockholm 171 76, Sweden.
20
Maritime Medical Genetics Service, IWK Health Centre, Halifax, NS B3K 6R8, Canada.
21
King's College London, Department of Medical & Molecular Genetics, Guy's Hospital, London WC2R 2LS, UK.
22
Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
23
West Middlesex University Hospital, Isleworth, Middlesex TW7 6AF, UK; Hospital of St John & St Elizabeth, London NW8 9NH, UK.
24
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.
25
Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria. Electronic address: johannes.zschocke@i-med.ac.at.

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.

PMID:
27745832
PMCID:
PMC5097948
DOI:
10.1016/j.ajhg.2016.08.019
[Indexed for MEDLINE]
Free PMC Article

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