Kapferer-Seebacher, Ines, Pepin, Melanie, Werner, Roland, Aitman, Timothy J., Nordgren, Ann ORCID: 0000-0003-3285-4281, Stoiber, Heribert, Thielens, Nicole, Gaboriaud, Christine, Amberger, Albert, Schossig, Anna, Gruber, Robert, Giunta, Cecilia ORCID: 0000-0002-9313-8257, Bamshad, Michael, Bjorck, Erik ORCID: 0000-0002-1210-2245, Chen, Christina, Chitayat, David, Dorschner, Michael, Schmitt-Egenolf, Marcus ORCID: 0000-0002-3858-8474, Hale, Christopher J., Hanna, David, Hennies, Hans Christian, Heiss-Kisielewsky, Irene, Lindstrand, Anna, Lundberg, Pernilla, Mitchell, Anna L., Nickerson, Deborah A., Reinstein, Eyal, Rohrbach, Marianne ORCID: 0000-0002-4013-6012, Romani, Nikolaus ORCID: 0000-0003-1614-9128, Schmuth, Matthias ORCID: 0000-0002-4064-1334, Silver, Rachel, Taylan, Fulya ORCID: 0000-0002-2907-0235, Vandersteen, Anthony, Vandrovcova, Jana, Weerakkody, Ruwan, Yang, Margaret, Pope, F. Michael, Byers, Peter H. and Zschocke, Johannes ORCID: 0000-0002-0046-8274 (2016). Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement. Am. J. Hum. Genet., 99 (5). S. 1005 - 1015. CAMBRIDGE: CELL PRESS. 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: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kapferer-Seebacher, InesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pepin, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Werner, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aitman, Timothy J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nordgren, AnnUNSPECIFIEDorcid.org/0000-0003-3285-4281UNSPECIFIED
Stoiber, HeribertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thielens, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gaboriaud, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amberger, AlbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schossig, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gruber, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giunta, CeciliaUNSPECIFIEDorcid.org/0000-0002-9313-8257UNSPECIFIED
Bamshad, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bjorck, ErikUNSPECIFIEDorcid.org/0000-0002-1210-2245UNSPECIFIED
Chen, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chitayat, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dorschner, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt-Egenolf, MarcusUNSPECIFIEDorcid.org/0000-0002-3858-8474UNSPECIFIED
Hale, Christopher J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hanna, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hennies, Hans ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heiss-Kisielewsky, IreneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindstrand, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lundberg, PernillaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mitchell, Anna L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nickerson, Deborah A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinstein, EyalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rohrbach, MarianneUNSPECIFIEDorcid.org/0000-0002-4013-6012UNSPECIFIED
Romani, NikolausUNSPECIFIEDorcid.org/0000-0003-1614-9128UNSPECIFIED
Schmuth, MatthiasUNSPECIFIEDorcid.org/0000-0002-4064-1334UNSPECIFIED
Silver, RachelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taylan, FulyaUNSPECIFIEDorcid.org/0000-0002-2907-0235UNSPECIFIED
Vandersteen, AnthonyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vandrovcova, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weerakkody, RuwanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, MargaretUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pope, F. MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Byers, Peter H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zschocke, JohannesUNSPECIFIEDorcid.org/0000-0002-0046-8274UNSPECIFIED
URN: urn:nbn:de:hbz:38-255969
DOI: 10.1016/j.ajhg.2016.08.019
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 99
Number: 5
Page Range: S. 1005 - 1015
Date: 2016
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SYNDROME TYPE-VIII; HETEROGENEOUS DISORDER; PROTEOLYTIC CLEAVAGE; GINGIVAL FLUID; ACTIVATION; EXPRESSION; COMPONENT; COLLAGEN; GENE; IDENTIFICATIONMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/25596

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