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.

Periodontal Ehlers–Danlos syndrome is associated with leukoencephalopathy

“…The identified C1R mutation c.149_150TC>AT (p.Val50Asp) segregated with 15 individuals clinically affected by periodontal EDS in this family; in Fig. 1, only individuals relevant for the present study are depicted, with the same numbers as used in Kapferer-Seebacher et al [1]. Individuals B:III-2, B:III-10, B:IV-1, B:IV-2, and B:IV-10 were available for the present neurologic analysis.…”

“…Family A was investigated at the VU University Medical Center, Amsterdam, in 2017. Clinical and genetic data of Family B have been previously reported by Kapferer-Seebacher et al [1]. Neurologic investigation of family B was conducted in 2017 and 2018 at the Medical University of Innsbruck, Austria.…”

“…Periodontal EDS is caused by heterozygous mutations in C1R or C1S [1], which encode subunits C1r and C1s of the first component of the classical complement pathway. This pathway is central in microbial–host interactions.…”

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“…Type VIII may be linked with a region on chromosome 12p13 [79]. Another study found that mutations in C1R or C1S may be responsible for Periodontal Ehlers-Danlos syndrome [77].…”

“…Type IV has an autosomal dominant/recessive pattern and type VIII has an autosomal dominant pattern with a prevalence 1 in 50000 [75]. Type IV and VIII are characterized by skin hyperextensibility, fragility, scarring, joint hypermobility, normal to slightly increased bruising on mild trauma, early-onset periodontitis, gingival recessions and thin gingiva and/or absence of attached gingiva [77]. Type IV except from the previous manifestations, presents a life-threatening visceral and large vessel rupture [5,21].…”