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

Ines Kapferer-Seebacher, Irene Heiss-Kisielewsky, Melanie Pepin, Michael Dorschner, Christopher J. Hale, David Hanna, Margaret Yang, Peter H. Byers, Roland Werner, Albert Amberger, Anna Schossig, Robert Gruber, Johannes Zschocke, Timothy J. Aitman, Timothy J. Aitman, Ann Nordgren, Erik Björck, Anna Lindstrand, Fulya Taylan, Ann Nordgren & 47 others Erik Björck, Anna Lindstrand, Heribert Stoiber, Nicole Thielens, Christine Gaboriaud, Robert Gruber, Nikolaus Romani, Matthias Schmuth, Cecilia Giunta, Marianne Rohrbach, Michael Bamshad, Michael Bamshad, Christina Chen, Deborah A. Nickerson, Michael Bamshad, Michael Bamshad, David Chitayat, Rachel Silver, David Chitayat, Rachel Silver, Marcus Schmitt-Egenolf, Hans Christian Hennies, Pernilla Lundberg, Anna L. Mitchell, Eyal Reinstein, Anthony Vandersteen, Jana Vandrovcova, Ruwan Weerakkody, F. Michael Pope, F. Michael Pope, Peter H. Byers, Kirk Aleck, Zoltan Banki, Joszef Dudas, Herbert Dumfahrt, Hady Haririan, James K. Hartsfield, Charles N. Kagen, Uschi Lindert, Thomas Meitinger, Wilfried Posch, Christian Pritz, David Ross, Richard J. Schroer, Georg Wick, Robert Wildin, Doris Wilflingseder

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1005-1014
Number of pages10
JournalAmerican Journal of Human Genetics
Volume99
Issue number5
Early online date13 Oct 2016
DOIs
Publication statusPublished - 3 Nov 2016

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Complement C1r
Complement C1s
Ehlers-Danlos Syndrome
Mutation
Classical Complement Pathway
INDEL Mutation
Aggressive Periodontitis
Joint Instability
Tooth Loss
Skin
Hyperpigmentation
Periodontitis
Gingiva
Endoplasmic Reticulum
Connective Tissue
Genes
Blood Vessels
Homeostasis

Cite this

Kapferer-Seebacher, I., Heiss-Kisielewsky, I., Pepin, M., Dorschner, M., Hale, C. J., Hanna, D., ... Wilflingseder, D. (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(5), 1005-1014. https://doi.org/10.1016/j.ajhg.2016.08.019
Kapferer-Seebacher, Ines ; Heiss-Kisielewsky, Irene ; Pepin, Melanie ; Dorschner, Michael ; Hale, Christopher J. ; Hanna, David ; Yang, Margaret ; Byers, Peter H. ; Werner, Roland ; Amberger, Albert ; Schossig, Anna ; Gruber, Robert ; Zschocke, Johannes ; Aitman, Timothy J. ; Aitman, Timothy J. ; Nordgren, Ann ; Björck, Erik ; Lindstrand, Anna ; Taylan, Fulya ; Nordgren, Ann ; Björck, Erik ; Lindstrand, Anna ; Stoiber, Heribert ; Thielens, Nicole ; Gaboriaud, Christine ; Gruber, Robert ; Romani, Nikolaus ; Schmuth, Matthias ; Giunta, Cecilia ; Rohrbach, Marianne ; Bamshad, Michael ; Bamshad, Michael ; Chen, Christina ; Nickerson, Deborah A. ; Bamshad, Michael ; Bamshad, Michael ; Chitayat, David ; Silver, Rachel ; Chitayat, David ; Silver, Rachel ; Schmitt-Egenolf, Marcus ; Hennies, Hans Christian ; Lundberg, Pernilla ; Mitchell, Anna L. ; Reinstein, Eyal ; Vandersteen, Anthony ; Vandrovcova, Jana ; Weerakkody, Ruwan ; Pope, F. Michael ; Pope, F. Michael ; Byers, Peter H. ; Aleck, Kirk ; Banki, Zoltan ; Dudas, Joszef ; Dumfahrt, Herbert ; Haririan, Hady ; Hartsfield, James K. ; Kagen, Charles N. ; Lindert, Uschi ; Meitinger, Thomas ; Posch, Wilfried ; Pritz, Christian ; Ross, David ; Schroer, Richard J. ; Wick, Georg ; Wildin, Robert ; Wilflingseder, Doris. / Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 5. pp. 1005-1014.
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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.",
author = "Ines Kapferer-Seebacher and Irene Heiss-Kisielewsky and Melanie Pepin and Michael Dorschner and Hale, {Christopher J.} and David Hanna and Margaret Yang and Byers, {Peter H.} and Roland Werner and Albert Amberger and Anna Schossig and Robert Gruber and Johannes Zschocke and Aitman, {Timothy J.} and Aitman, {Timothy J.} and Ann Nordgren and Erik Bj{\"o}rck and Anna Lindstrand and Fulya Taylan and Ann Nordgren and Erik Bj{\"o}rck and Anna Lindstrand and Heribert Stoiber and Nicole Thielens and Christine Gaboriaud and Robert Gruber and Nikolaus Romani and Matthias Schmuth and Cecilia Giunta and Marianne Rohrbach and Michael Bamshad and Michael Bamshad and Christina Chen and Nickerson, {Deborah A.} and Michael Bamshad and Michael Bamshad and David Chitayat and Rachel Silver and David Chitayat and Rachel Silver and Marcus Schmitt-Egenolf and Hennies, {Hans Christian} and Pernilla Lundberg and Mitchell, {Anna L.} and Eyal Reinstein and Anthony Vandersteen and Jana Vandrovcova and Ruwan Weerakkody and Pope, {F. Michael} and Pope, {F. Michael} and Byers, {Peter H.} and Kirk Aleck and Zoltan Banki and Joszef Dudas and Herbert Dumfahrt and Hady Haririan and Hartsfield, {James K.} and Kagen, {Charles N.} and Uschi Lindert and Thomas Meitinger and Wilfried Posch and Christian Pritz and David Ross and Schroer, {Richard J.} and Georg Wick and Robert Wildin and Doris Wilflingseder",
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Kapferer-Seebacher, I, Heiss-Kisielewsky, I, Pepin, M, Dorschner, M, Hale, CJ, Hanna, D, Yang, M, Byers, PH, Werner, R, Amberger, A, Schossig, A, Gruber, R, Zschocke, J, Aitman, TJ, Aitman, TJ, Nordgren, A, Björck, E, Lindstrand, A, Taylan, F, Nordgren, A, Björck, E, Lindstrand, A, Stoiber, H, Thielens, N, Gaboriaud, C, Gruber, R, Romani, N, Schmuth, M, Giunta, C, Rohrbach, M, Bamshad, M, Bamshad, M, Chen, C, Nickerson, DA, Bamshad, M, Bamshad, M, Chitayat, D, Silver, R, Chitayat, D, Silver, R, Schmitt-Egenolf, M, Hennies, HC, Lundberg, P, Mitchell, AL, Reinstein, E, Vandersteen, A, Vandrovcova, J, Weerakkody, R, Pope, FM, Pope, FM, Byers, PH, Aleck, K, Banki, Z, Dudas, J, Dumfahrt, H, Haririan, H, Hartsfield, JK, Kagen, CN, Lindert, U, Meitinger, T, Posch, W, Pritz, C, Ross, D, Schroer, RJ, Wick, G, Wildin, R & Wilflingseder, D 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, vol. 99, no. 5, pp. 1005-1014. https://doi.org/10.1016/j.ajhg.2016.08.019

Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement. / Kapferer-Seebacher, Ines; Heiss-Kisielewsky, Irene; Pepin, Melanie; Dorschner, Michael; Hale, Christopher J.; Hanna, David; Yang, Margaret; Byers, Peter H.; Werner, Roland; Amberger, Albert; Schossig, Anna; Gruber, Robert; Zschocke, Johannes; Aitman, Timothy J.; Aitman, Timothy J.; Nordgren, Ann; Björck, Erik; Lindstrand, Anna; Taylan, Fulya; Nordgren, Ann; Björck, Erik; Lindstrand, Anna; Stoiber, Heribert; Thielens, Nicole; Gaboriaud, Christine; Gruber, Robert; Romani, Nikolaus; Schmuth, Matthias; Giunta, Cecilia; Rohrbach, Marianne; Bamshad, Michael; Bamshad, Michael; Chen, Christina; Nickerson, Deborah A.; Bamshad, Michael; Bamshad, Michael; Chitayat, David; Silver, Rachel; Chitayat, David; Silver, Rachel; Schmitt-Egenolf, Marcus; Hennies, Hans Christian; Lundberg, Pernilla; Mitchell, Anna L.; Reinstein, Eyal; Vandersteen, Anthony; Vandrovcova, Jana; Weerakkody, Ruwan; Pope, F. Michael; Pope, F. Michael; Byers, Peter H.; Aleck, Kirk; Banki, Zoltan; Dudas, Joszef; Dumfahrt, Herbert; Haririan, Hady; Hartsfield, James K.; Kagen, Charles N.; Lindert, Uschi; Meitinger, Thomas; Posch, Wilfried; Pritz, Christian; Ross, David; Schroer, Richard J.; Wick, Georg; Wildin, Robert; Wilflingseder, Doris.

In: American Journal of Human Genetics, Vol. 99, No. 5, 03.11.2016, p. 1005-1014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement

AU - Kapferer-Seebacher, Ines

AU - Heiss-Kisielewsky, Irene

AU - Pepin, Melanie

AU - Dorschner, Michael

AU - Hale, Christopher J.

AU - Hanna, David

AU - Yang, Margaret

AU - Byers, Peter H.

AU - Werner, Roland

AU - Amberger, Albert

AU - Schossig, Anna

AU - Gruber, Robert

AU - Zschocke, Johannes

AU - Aitman, Timothy J.

AU - Aitman, Timothy J.

AU - Nordgren, Ann

AU - Björck, Erik

AU - Lindstrand, Anna

AU - Taylan, Fulya

AU - Nordgren, Ann

AU - Björck, Erik

AU - Lindstrand, Anna

AU - Stoiber, Heribert

AU - Thielens, Nicole

AU - Gaboriaud, Christine

AU - Gruber, Robert

AU - Romani, Nikolaus

AU - Schmuth, Matthias

AU - Giunta, Cecilia

AU - Rohrbach, Marianne

AU - Bamshad, Michael

AU - Bamshad, Michael

AU - Chen, Christina

AU - Nickerson, Deborah A.

AU - Bamshad, Michael

AU - Bamshad, Michael

AU - Chitayat, David

AU - Silver, Rachel

AU - Chitayat, David

AU - Silver, Rachel

AU - Schmitt-Egenolf, Marcus

AU - Hennies, Hans Christian

AU - Lundberg, Pernilla

AU - Mitchell, Anna L.

AU - Reinstein, Eyal

AU - Vandersteen, Anthony

AU - Vandrovcova, Jana

AU - Weerakkody, Ruwan

AU - Pope, F. Michael

AU - Pope, F. Michael

AU - Byers, Peter H.

AU - Aleck, Kirk

AU - Banki, Zoltan

AU - Dudas, Joszef

AU - Dumfahrt, Herbert

AU - Haririan, Hady

AU - Hartsfield, James K.

AU - Kagen, Charles N.

AU - Lindert, Uschi

AU - Meitinger, Thomas

AU - Posch, Wilfried

AU - Pritz, Christian

AU - Ross, David

AU - Schroer, Richard J.

AU - Wick, Georg

AU - Wildin, Robert

AU - Wilflingseder, Doris

PY - 2016/11/3

Y1 - 2016/11/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84997281837&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2016.08.019

DO - 10.1016/j.ajhg.2016.08.019

M3 - Article

VL - 99

SP - 1005

EP - 1014

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -