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

Kapferer-Seebacher, I. et al. (2016) Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement. American Journal of Human Genetics, 99. pp. 1-10. ISSN 1537-6605

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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.

Item Type: Article
Additional Information: Unmapped bibliographic data: ST - Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement [Field not mapped to EPrints] L1 - internal-pdf://4098462335/Kapferer-Seebac-2016-Periodontal Ehlers-Danlos.pdf [Field not mapped to EPrints] AD - Department of Operative and Restorative Dentistry, Medical University of Innsbruck, Innsbruck 6020, Austria. [Field not mapped to EPrints] AN - 27745832 [Field not mapped to EPrints]
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
R Medicine > RK Dentistry
R Medicine > RL Dermatology
Schools: School of Applied Sciences
Related URLs:
Depositing User: Hans Hennies
Date Deposited: 03 Nov 2016 14:09
Last Modified: 13 Oct 2017 18:49
URI: http://eprints.hud.ac.uk/id/eprint/29906

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