Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome

Anneke Kievit; Federico Tessadori; Hannie Douben; Ingrid Jordens; Madelon Maurice; Jeannette Hoogeboom; Raoul Hennekam; Sheela Nampoothiri; Hülya Kayserili; Marco Castori; Margo Whiteford; Connie Motter; Catherine Melver; Michael Cunningham; Anne Hing; Nancy M Kokitsu-Nakata; Siulan Vendramini-Pittoli; Antonio Richieri-Costa; Annette F Baas; Corstiaan C Breugem; Karen Duran; Maarten Massink; Patrick W B Derksen; Wilfred F J van IJcken; Leontine van Unen; Fernando Santos-Simarro; Pablo Lapunzina; Vera L Gil-da Silva Lopes; Elaine Lustosa-Mendes; Max Krall; Anne Slavotinek; Victor Martinez-Glez; Jeroen Bakkers; Koen L I van Gassen; Annelies de Klein; Marie-José H van den Boogaard; Gijs van Haaften

doi:10.1038/s41431-017-0010-5

Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome

Anneke Kievit, Federico Tessadori, Hannie Douben, Ingrid Jordens, Madelon Maurice, Jeannette Hoogeboom, Raoul Hennekam, Sheela Nampoothiri, Hülya Kayserili, Marco Castori, Margo Whiteford, Connie Motter, Catherine Melver, Michael Cunningham, Anne Hing, Nancy M Kokitsu-Nakata, Siulan Vendramini-Pittoli, Antonio Richieri-Costa, Annette F Baas, Corstiaan C BreugemKaren Duran, Maarten Massink, Patrick W B Derksen, Wilfred F J van IJcken, Leontine van Unen, Fernando Santos-Simarro, Pablo Lapunzina, Vera L Gil-da Silva Lopes, Elaine Lustosa-Mendes, Max Krall, Anne Slavotinek, Victor Martinez-Glez, Jeroen Bakkers, Koen L I van Gassen, Annelies de Klein, Marie-José H van den Boogaard, Gijs van Haaften

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

34 Citations (Scopus)

Abstract

Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.

Original language	English
Pages (from-to)	210-219
Number of pages	10
Journal	European Journal of Human Genetics
Volume	26
Issue number	2
DOIs	https://doi.org/10.1038/s41431-017-0010-5
Publication status	Published - Feb 2018

Keywords

Adolescent
Adult
Animals
Antigens, CD/genetics
Cadherins/genetics
Catenins/genetics
Cell Adhesion
Child
Child, Preschool
Cleft Lip/genetics
Cleft Palate/genetics
Ectropion/genetics
Female
Humans
MCF-7 Cells
Male
Mutation
Protein Binding
Tooth Abnormalities/genetics
Zebrafish

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Kievit, A., Tessadori, F., Douben, H., Jordens, I., Maurice, M., Hoogeboom, J., Hennekam, R., Nampoothiri, S., Kayserili, H., Castori, M., Whiteford, M., Motter, C., Melver, C., Cunningham, M., Hing, A., Kokitsu-Nakata, N. M., Vendramini-Pittoli, S., Richieri-Costa, A., Baas, A. F., ... van Haaften, G. (2018). Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome. European Journal of Human Genetics, 26(2), 210-219. https://doi.org/10.1038/s41431-017-0010-5

@article{86aaffdeedc4496daa9ce315d309043e,

title = "Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome",

abstract = "Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.",

keywords = "Adolescent, Adult, Animals, Antigens, CD/genetics, Cadherins/genetics, Catenins/genetics, Cell Adhesion, Child, Child, Preschool, Cleft Lip/genetics, Cleft Palate/genetics, Ectropion/genetics, Female, Humans, MCF-7 Cells, Male, Mutation, Protein Binding, Tooth Abnormalities/genetics, Zebrafish",

author = "Anneke Kievit and Federico Tessadori and Hannie Douben and Ingrid Jordens and Madelon Maurice and Jeannette Hoogeboom and Raoul Hennekam and Sheela Nampoothiri and H{\"u}lya Kayserili and Marco Castori and Margo Whiteford and Connie Motter and Catherine Melver and Michael Cunningham and Anne Hing and Kokitsu-Nakata, {Nancy M} and Siulan Vendramini-Pittoli and Antonio Richieri-Costa and Baas, {Annette F} and Breugem, {Corstiaan C} and Karen Duran and Maarten Massink and Derksen, {Patrick W B} and {van IJcken}, {Wilfred F J} and {van Unen}, Leontine and Fernando Santos-Simarro and Pablo Lapunzina and {Gil-da Silva Lopes}, {Vera L} and Elaine Lustosa-Mendes and Max Krall and Anne Slavotinek and Victor Martinez-Glez and Jeroen Bakkers and {van Gassen}, {Koen L I} and {de Klein}, Annelies and {van den Boogaard}, {Marie-Jos{\'e} H} and {van Haaften}, Gijs",

year = "2018",

month = feb,

doi = "10.1038/s41431-017-0010-5",

language = "English",

volume = "26",

pages = "210--219",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Nature Publishing Group",

number = "2",

}

Kievit, A, Tessadori, F, Douben, H, Jordens, I, Maurice, M, Hoogeboom, J, Hennekam, R, Nampoothiri, S, Kayserili, H, Castori, M, Whiteford, M, Motter, C, Melver, C, Cunningham, M, Hing, A, Kokitsu-Nakata, NM, Vendramini-Pittoli, S, Richieri-Costa, A, Baas, AF, Breugem, CC, Duran, K, Massink, M, Derksen, PWB, van IJcken, WFJ, van Unen, L, Santos-Simarro, F, Lapunzina, P, Gil-da Silva Lopes, VL, Lustosa-Mendes, E, Krall, M, Slavotinek, A, Martinez-Glez, V, Bakkers, J, van Gassen, KLI, de Klein, A, van den Boogaard, M-JH & van Haaften, G 2018, 'Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome', European Journal of Human Genetics, vol. 26, no. 2, pp. 210-219. https://doi.org/10.1038/s41431-017-0010-5

TY - JOUR

T1 - Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome

AU - Kievit, Anneke

AU - Tessadori, Federico

AU - Douben, Hannie

AU - Jordens, Ingrid

AU - Maurice, Madelon

AU - Hoogeboom, Jeannette

AU - Hennekam, Raoul

AU - Nampoothiri, Sheela

AU - Kayserili, Hülya

AU - Castori, Marco

AU - Whiteford, Margo

AU - Motter, Connie

AU - Melver, Catherine

AU - Cunningham, Michael

AU - Hing, Anne

AU - Kokitsu-Nakata, Nancy M

AU - Vendramini-Pittoli, Siulan

AU - Richieri-Costa, Antonio

AU - Baas, Annette F

AU - Breugem, Corstiaan C

AU - Duran, Karen

AU - Massink, Maarten

AU - Derksen, Patrick W B

AU - van IJcken, Wilfred F J

AU - van Unen, Leontine

AU - Santos-Simarro, Fernando

AU - Lapunzina, Pablo

AU - Gil-da Silva Lopes, Vera L

AU - Lustosa-Mendes, Elaine

AU - Krall, Max

AU - Slavotinek, Anne

AU - Martinez-Glez, Victor

AU - Bakkers, Jeroen

AU - van Gassen, Koen L I

AU - de Klein, Annelies

AU - van den Boogaard, Marie-José H

AU - van Haaften, Gijs

PY - 2018/2

Y1 - 2018/2

N2 - Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.

AB - Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.

KW - Adolescent

KW - Adult

KW - Animals

KW - Antigens, CD/genetics

KW - Cadherins/genetics

KW - Catenins/genetics

KW - Cell Adhesion

KW - Child

KW - Child, Preschool

KW - Cleft Lip/genetics

KW - Cleft Palate/genetics

KW - Ectropion/genetics

KW - Female

KW - Humans

KW - MCF-7 Cells

KW - Male

KW - Mutation

KW - Protein Binding

KW - Tooth Abnormalities/genetics

KW - Zebrafish

U2 - 10.1038/s41431-017-0010-5

DO - 10.1038/s41431-017-0010-5

M3 - Article

C2 - 29348693

SN - 1018-4813

VL - 26

SP - 210

EP - 219

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 2

ER -

Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome

Abstract

Keywords

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