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Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome

Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome
Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.

0964-6906
1900-1921
Alharatani, Reham
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Ververi, Athina
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Beleza‐Meireles, Ana
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Ji, Weizhen
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Emily, Mis
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Patterson, Quinten T
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Griffin, John N.
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Chang, Caitlin A
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Dixit, Abhijit
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Konstantino, Monica
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Healy, Christopher
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Hannan, Sumayyah
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Neo, Natsuko
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Cash, Alex
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Li, Dong
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Bhoj, Elizabeth
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Zackai, Elaine H.
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Cleaver, Ruth
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Baralle, Diana
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McEntagart, Meriel
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Newbury-Ecob, Ruth
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Scott, Richard
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Hurst, Jane A
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Au, Ping Yee Billie
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Hosey, Marie Therese
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Khokha, Mustafa
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Marciano, Denise K
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Lakhani, Saquib A
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Liu, Karen J
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Alharatani, Reham
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Ververi, Athina
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Beleza‐Meireles, Ana
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Ji, Weizhen
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Emily, Mis
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Patterson, Quinten T
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Griffin, John N.
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Chang, Caitlin A
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Dixit, Abhijit
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Konstantino, Monica
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Healy, Christopher
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Hannan, Sumayyah
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Neo, Natsuko
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Cash, Alex
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Li, Dong
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Bhoj, Elizabeth
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Zackai, Elaine H.
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Cleaver, Ruth
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Baralle, Diana
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McEntagart, Meriel
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Newbury-Ecob, Ruth
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Scott, Richard
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Hurst, Jane A
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Au, Ping Yee Billie
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Hosey, Marie Therese
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Khokha, Mustafa
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Marciano, Denise K
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Lakhani, Saquib A
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Liu, Karen J
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Alharatani, Reham, Ververi, Athina, Beleza‐Meireles, Ana, Ji, Weizhen, Emily, Mis, Patterson, Quinten T, Griffin, John N., Chang, Caitlin A, Dixit, Abhijit, Konstantino, Monica, Healy, Christopher, Hannan, Sumayyah, Neo, Natsuko, Cash, Alex, Li, Dong, Bhoj, Elizabeth, Zackai, Elaine H., Cleaver, Ruth, Baralle, Diana, McEntagart, Meriel, Newbury-Ecob, Ruth, Scott, Richard, Hurst, Jane A, Au, Ping Yee Billie, Hosey, Marie Therese, Khokha, Mustafa, Marciano, Denise K, Lakhani, Saquib A and Liu, Karen J (2020) Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome. Human Molecular Genetics, 29 (11), 1900-1921. (doi:10.1093/hmg/ddaa050).

Record type: Article

Abstract

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.

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Alharatani_p120_HMG-FINAL - Accepted Manuscript
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Accepted/In Press date: 16 March 2020
e-pub ahead of print date: 20 March 2020
Published date: 1 June 2020
Additional Information: © The Author(s) 2020. Published by Oxford University Press.

Identifiers

Local EPrints ID: 438855
URI: http://eprints.soton.ac.uk/id/eprint/438855
ISSN: 0964-6906
PURE UUID: edd858e0-06a2-4cc3-9781-7191e2ab34e9
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

Catalogue record

Date deposited: 25 Mar 2020 17:32
Last modified: 18 Jun 2021 01:40

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Contributors

Author: Reham Alharatani
Author: Athina Ververi
Author: Ana Beleza‐Meireles
Author: Weizhen Ji
Author: Mis Emily
Author: Quinten T Patterson
Author: John N. Griffin
Author: Caitlin A Chang
Author: Abhijit Dixit
Author: Monica Konstantino
Author: Christopher Healy
Author: Sumayyah Hannan
Author: Natsuko Neo
Author: Alex Cash
Author: Dong Li
Author: Elizabeth Bhoj
Author: Elaine H. Zackai
Author: Ruth Cleaver
Author: Diana Baralle ORCID iD
Author: Meriel McEntagart
Author: Ruth Newbury-Ecob
Author: Richard Scott
Author: Jane A Hurst
Author: Ping Yee Billie Au
Author: Marie Therese Hosey
Author: Mustafa Khokha
Author: Denise K Marciano
Author: Saquib A Lakhani
Author: Karen J Liu

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