The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.
Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S , which Encode Subcomponents C1r and C1s of Complement
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“In 93 individuals with C1R or C1S mutations reported by Kapferer-Seebacher et al. [2016] joint hypermobility was reported in 56% of patients, mostly affecting the fingers (30%), the elbows (19%), knees (11%), hips, wrist, and ankle (3%).”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Marfanoid habitus, scoliosis, osteoarthritis, flat feet, and hernia were not consistent features [Kapferer-Seebacher et al., 2016].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Atrophic scars were present in 50% of cases [Kapferer-Seebacher et al., 2016].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Kapferer-Seebacher et al. [2016] reported a prevalence of 16% for vascular complications (cerebral aneurisms or aortic dissection), and one individual with three events of organ rupture (once duodenum, twice lung).”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Heterozygous missense or in-frame insertion/deletion variants in C1R were detected in 15 families (comprising 76 affected individuals), and heterozygous missense or in-frame insertion/ deletion variants in C1S were detected in two families (comprising 16 affected individuals).”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Additionally, patients' fibroblasts showed an increased proportion of dilated rough ER (RER) cisternae [Reinstein et al., 2012;Kapferer-Seebacher et al., 2016].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“There were single patients with autoimmunologic disorders like Sj€ ogren syndrome, rosacea, and Crohn's disease [Kapferer-Seebacher et al., 2016].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In 17 of these families, heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (two families) were identified.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“Variants never involved the catalytic domain of C1r or C1s [Kapferer-Seebacher et al., 2016].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“A characteristic recently described feature is a striking lack of attached gingiva causing oral tissue fragility (Fig. 1) [Kapferer-Seebacher et al., 2016].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“In 2016, an international consortium published 19 independent families comprising 107 individuals with pEDS to identify the genetic locus [Kapferer-Seebacher et al., 2016].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“Biochemical analysis of collagen in cultured skin fibroblasts did not show abnormalities in the production and secretion of type I, III, and V collagens in several case reports and also in eight individuals with confirmed mutations in C1S/C1R [Biesecker et al., 1991;Cunniff and Williamson-Kruse, 1995;Kapferer-Seebacher et al., 2016].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“In 93 individuals with C1R or C1S mutations reported by Kapferer-Seebacher et al. [2016], consistent cutaneous findings were pretibial discolorations (83%), easy bruising (96%), skin fragility (83%), and (mild) hyperelasticity of the skin (73%).”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“Electron microscopy examination of skin reported in seven individuals with C1R/C1S mutations showed decreased collagen content, abnormal variation in collagen fibril diameter and some abnormally shaped fibrils [Rahman et al., 2003;Reinstein et al., 2012Reinstein et al., , 2013;;Kapferer-Seebacher et al., 2016], which is in line with further reports [Kobayasi, 2004;Mataix et al., 2008].”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
The cited source says what the claim attributes to it.
In the citing paper
“Kapferer-Seebacher et al. [2016] reported a prevalence of 40% for recurrent infections like otitis media, herpes zoster, bladder infections, empyema, kidney infections, or pneumonia.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kapferer-Seebacher et al., 2016
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The PyMOL Molecular Graphics System
DeLano, W. L. (2002) · Medical Entomology and Zoology · Cited by 18,147
Peer Bork, B., & Beckmann, G. (1993) · Journal of Molecular Biology · doi:10.1006/jmbi.1993.1305 · Cited by 582
Bonadio, J. F., & Byers, P. H. (1985) · Nature · doi:10.1038/316363a0 · Cited by 194
Self-citationAggressive periodontitis: case definition and diagnostic criteria
Albandar, J. M. (2014) · Periodontology 2000 · doi:10.1111/prd.12014 · Cited by 183
The bradykinin-forming cascade and its role in hereditary angioedema
Kaplan, A. P., & Joseph, K. (2010) · Annals of Allergy Asthma & Immunology · doi:10.1016/j.anai.2010.01.007 · Cited by 165
Steiglitz, B. M., Keene, D. R., & Greenspan, D. S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m209891200 · Cited by 165
Baumann, M., Giunta, C., Krabichler, B., Rüschendorf, F., Zoppi, N., Colombi, M., Bittner, R. E., Quijano-Roy, S., Muntoni, F., Cirak, S., et al. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.12.004 · Cited by 162
Self-citationFrank, I., Piatak, M., Stoessel, H., Romani, N., Bonnyay, D., Lifson, J. D., & Pope, M. (2002) · Journal of Virology · doi:10.1128/jvi.76.6.2936-2951.2002 · Cited by 137
Self-citationMaekawa, T., Abe, T., Hajishengallis, E., Hosur, K. B., DeAngelis, R. A., Ricklin, D., Lambris, J. D., & Hajishengallis, G. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400569 · Cited by 115
Budayova‐Spano, M., Lacroix, M., Thielens, N. M., Arlaud, G. J., Fontecilla‐Camps, J. C., & Gaboriaud, C. (2002) · The EMBO Journal · doi:10.1093/emboj/21.3.231 · Cited by 111
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Items 101–123 of 123
Periodontal Disease Associated with Genetic Disorders
Wu, J., Leung, W. K., & Sun, W. (2021) · Dentistry · doi:10.5772/intechopen.97497
Grumach, A. S. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.737232141.793571790
Periodontitis as a Manifestation of Systemic Disease
Moharamzadeh, K. (2018) · Wiley eBooks · doi:10.1002/9781119312093.ch43
Oral Pathology and Oral Medicine
Chaar, E. E., & Kumar, A. M. (2022) · Wiley eBooks · doi:10.1002/9781119793588.ch4
Infectious Complications of Complement Deficiency and Diseases of Its Dysregulation
Sullivan, K. E., & Frank, M. M. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-75608-2.00103-8
Will a hyperactive classical complement pathway exacerbate autoimmune diseases?
Okrój, M., & de Córdoba, S. R. (2022) · Autoimmunity Reviews · doi:10.1016/j.autrev.2022.103241
Infections in primary immunodeficiency
Kline, A., & Zerbe, C. S. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-95061-9.00028-x
Baykal, S., Yıldız, T., Gürbüz, G., & Tozkır, H. (2023) · Clinical Dysmorphology · doi:10.1097/mcd.0000000000000441
Collagen V Promotes Fibroblast Contractility, And Adhesion Formation, And Stability
Royer, S. P. (2023) · Digital Commons - Michigan Tech (Michigan Technological University) · doi:10.37099/mtu.dc.etdr/1647
Gum bleeding and early tooth loss
Hanisch, M. R., Zschocke, J., & Kapferer‐Seebacher, I. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95082-4.00010-4
Self-citationGenetic Disorders of Collagen, Elastin and Dermal Matrix
Burrows, N. (2024) · Wiley eBooks · doi:10.1002/9781119709268.rook070
Stretching Boundaries: A Comprehensive Review of Ehlers-Danlos Syndrome and its Subtypes
Sheth, S., Oturkar, I., & Kizhakethil, M. M. (2024) · International Journal of Genetic Modifications and Recombinations · doi:10.37591/ijgmr.v02i01.136244
Ehlers-Danlos syndrome: From bedside to bench
(2024) · Frontiers research topics · doi:10.3389/978-2-8325-4557-7
Collagenopathies – The Ehlers-Danlos syndromes
Malfait, F. (2024) · Elsevier eBooks · doi:10.1016/b978-0-12-822951-4.00011-4
Violaceous Pretibial Plaques: A Clue to Periodontal Variant of Ehlers-Danlos Syndrome
Turkia, H. B., Alsabbagh, M., Burshaid, D., Baili, Y., & Almutawea, L. (2026) · Fetal and Pediatric Pathology · doi:10.1080/15513815.2025.2590051
Baranovskaya, E. V., Rumyantseva, V. A., Bukaeva, A. A., Ershova, A. I., Meshkov, A. N., & М., Д. О. (2026) · CARDIOVASCULAR THERAPY AND PREVENTION · doi:10.15829/1728-8800-20254669
Abad, J. D., Zulaika-Lloret, M., del Pino, G. F., & Fernández, F. A. (2026) · Medicina Clínica · doi:10.1016/j.medcli.2026.107423
Dialogue entre le complément C1 et l'alarmine HMGB1 dans l'inflammation
Lorvellec, M. (2024) · theses.fr (ABES) · doi:10.70675/0098aa7azc426z4ad1zb78czeee46320fdb2
Abad, J. D., Zulaika-Lloret, M., del Pino, G. F., & Fernández, F. A. (2026) · Medicina Clínica (English Edition) · doi:10.1016/j.medcle.2026.107423
Kowalewska, P. M., Yin, H. R., Wang, M., Balint, B., Hoveyda, S., Manian, U., Zhao, P., Samsoondar, J. P., Fan, K. Y., Nong, Z., et al. (2026) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.126.324690
Shadid, A., Rich, H. E., Hok, K. D., Doursout, M., Restrepo, M. I., Banda, N. K., Gunamalai, L., & Shivshankar, P. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27135877
Dörfer, C., Geiken, A., & Graetz, C. (2023) · Elsevier eBooks · doi:10.1016/b978-3-437-23801-7.00015-x
Haut, N., Rossi, V., Peliconi, J., Reiser, J., Thielens, N. M., Roumenina, L. T., & Gaboriaud, C. (2026) · Antibodies · doi:10.3390/antib15050092
Self-citation
Metadata
- Authors
- Kapferer-Seebacher, I., Pepin, M., Werner, R., Aitman, T. J., Nordgren, A., Stoiber, H., Thielens, N., Gaboriaud, C., Amberger, A., Schossig, A., Gruber, R., Giunta, C., Bamshad, M., Björck, E., Chen, C., Chitayat, D., Dorschner, M., Schmitt-Egenolf, M., Hale, C. J., Hanna, D., Hennies, H. C., Heiss-Kisielewsky, I., Lindstrand, A., Lundberg, P., Mitchell, A. L., Nickerson, D. A., Reinstein, E., Rohrbach, M., Romani, N., Schmuth, M., Silver, R., Taylan, F., Vandersteen, A., Vandrovcova, J., Weerakkody, R., Yang, M., Pope, F. M., Byers, P. H., Zschocke, J., Aleck, K., Banki, Z., Dudas, J., Dumfahrt, H., Haririan, H., Hartsfield, J. K., Kagen, C. N., Lindert, U., Meitinger, T., Posch, W., Pritz, C., Ross, D., Schroer, R. J., Wick, G., Wildin, R., & Wilflingseder, D.
- Affiliations
- University of Washington (US)
- Innsbruck Medical University (AT)
- Institute of Genetics and Cancer (GB)
- Karolinska University Hospital (SE)
- Centre National de la Recherche Scientifique (FR)
- University Children's Hospital Zurich (CH)
- Mount Sinai Hospital (CA)
- University of Huddersfield (GB)
- Umeå University (SE)
- Case Western Reserve University (US)
- Meir Medical Center (IL)
- Karolinska Institutet (SE)
- Izaak Walton Killam Health Centre (CA)
- Imperial College London (GB)
- West Middlesex University Hospital (GB)
- Corresponding author
- Byers, Peter H.
- Zschocke, Johannes
- ORCID
- Aitman, Timothy J.
- Nordgren, Ann
- Stoiber, Heribert
- Thielens, Nicole
- Gaboriaud, Christine
- Gruber, Robert
- Giunta, Cecilia
- Bamshad, Michael
- Björck, Erik
- Chitayat, David
- Hennies, Hans Christian
- Lindstrand, Anna
- Lundberg, Pernilla
- Mitchell, Anna L.
- Nickerson, Deborah A.
- Reinstein, Eyal
- Rohrbach, Marianne
- Romani, Nikolaus
- Schmuth, Matthias
- Taylan, Fulya
- Weerakkody, Ruwan
- Yang, Margaret
- Byers, Peter H.
- Zschocke, Johannes
- Haririan, Hady
- Hartsfield, James K.
- Lindert, Uschi
- Meitinger, Thomas
- Posch, Wilfried
- Pritz, Christian
- Ross, David
- Wildin, Robert
- Wilflingseder, Doris
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 99
- Issue
- 5
- Pages
- 1005-1014
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC5097948
- OpenAlex
- W2531200591
- Cited by
- 123
- References
- 40
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 10 · 2023: 11 · 2022: 20 · 2021: 14 · 2020: 18 · 2019: 15 · 2018: 13 · 2017: 10
- FWCI
- 7.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The American Journal of Human Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- UWA Profiles and Research Repository (UWA) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- HAL (submittedVersion, other-oa)
- University of Huddersfield Repository (University of Huddersfield) (submittedVersion)
- DiVA at Umeå University (Umeå University) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Huddersfield Research Portal (University of Huddersfield) (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Oesterreichische Nationalbank (15408)
- Propter Homines Foundation
- FWF (W1253-B24)
- SNF (310030_138288)
- UK MRC Clinical Sciences Centre
- Wellcome Clinical Training Fellowship (100565/Z/12/Z)
- Freudmann Fund for Translational Research in Ehlers Danlos syndrome, the Ehlers Danlos Research Fund, and the Center for Precision Diagnostics at the University of Washington
- National Heart, Lung, and Blood Institute (U54HG006493)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Health Sciences › Dentistry › Periodontics › Oral and gingival health research
- Keywords
- C1r, C1s, classical complement pathway, C1q, missense mutations, insertion-deletion mutations, periodontitis, endoplasmic reticulum retention, autosomal dominant disorder, gene mapping, joint hypermobility, skin fragility
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 12, Complement C1s, Ehlers-Danlos Syndrome, Endoplasmic Reticulum, Female, Humans, Male, Pedigree, Periodontitis, Protein Conformation, Complement C1r, Gene Deletion, Mutation, Missense, Young Adult, Genetic Loci, Exome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
