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Recurrent mutations in the basic domain of TWIST2 cause ablepharon macrostomia and Barber-Say syndromes

Shannon Marchegiani, Taylor Davis, Federico Tessadori, Gijs van Haaften, Francesco Brancati, Alexander Hoischen, Haigen Huang, Elise Valkanas, Barbara Pusey, Denny Schanze, et al. (2015) AMERICAN JOURNAL OF HUMAN GENETICS. 97(1). p.99-110
abstract
Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TW1ST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-1'WIST2 in HeLa cells. Comparison of wild-type and mutant TW1ST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TW1ST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
EPITHELIAL-MESENCHYMAL TRANSITION, MORPHOLOGY STANDARD TERMINOLOGY, AUTOSOMAL-DOMINANT INHERITANCE, SAETHRE-CHOTZEN SYNDROME, SETLEIS SYNDROME, ATROPHIC SKIN, UNDIAGNOSED DISEASES, TRANSCRIPTION FACTOR, FRAMESHIFT MUTATION, FAMILIAL OCCURRENCE
journal title
AMERICAN JOURNAL OF HUMAN GENETICS
Am. J. Hum. Genet.
volume
97
issue
1
pages
99 - 110
Web of Science type
Article
Web of Science id
000358189500009
JCR category
GENETICS & HEREDITY
JCR impact factor
10.794 (2015)
JCR rank
8/165 (2015)
JCR quartile
1 (2015)
ISSN
0002-9297
DOI
10.1016/j.ajhg.2015.05.017
language
English
UGent publication?
yes
classification
A1
additional info
the first three authors contributed equally to this work; the last two authors contributed equally to this work and are co-senior authors
copyright statement
I have transferred the copyright for this publication to the publisher
id
7260803
handle
http://hdl.handle.net/1854/LU-7260803
date created
2016-06-17 15:21:28
date last changed
2016-12-19 15:47:14
@article{7260803,
  abstract     = {Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TW1ST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-1'WIST2 in HeLa cells. Comparison of wild-type and mutant TW1ST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TW1ST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.},
  author       = {Marchegiani, Shannon and Davis, Taylor and Tessadori, Federico and van Haaften, Gijs and Brancati, Francesco and Hoischen, Alexander and Huang, Haigen and Valkanas, Elise and Pusey, Barbara and Schanze, Denny and Venselaar, Hanka and Vulto-van Silfhout, Anneke T and Wolfe, Lynne A and Tifft, Cynthia J and Zerfas, Patricia M and Zambruno, Giovanna and Kariminejad, Ariana and Sabbagh-Kermani, Farahnaz and Lee, Janice and Tsokos, Maria G and Lee, Chyi-Chia R and Ferraz, Victor and da Silva, Eduarda Morgana and Stevens, Cathy A and ROCHE, NATHALIE and Bartsch, Oliver and Farndon, Peter and Bermejo-Sanchez, Eva and Brooks, Brian P and Maduro, Valerie and Dallapiccola, Bruno and Ramos, Feliciano J and Chung, Hon-Yin Brian and Le Caignec, C{\'e}dric and Martins, Fabiana and Jacyk, Witold K and Mazzanti, Laura and Brunner, Han G and Bakkers, Jeroen and Lin, Shuo and Malicdan, May Christine V and Boerkoel, Cornelius F and Gahl, William A and de Vries, Bert BA and van Haelst, Mieke M and Zenker, Martin and Markello, Thomas C},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {EPITHELIAL-MESENCHYMAL TRANSITION,MORPHOLOGY STANDARD TERMINOLOGY,AUTOSOMAL-DOMINANT INHERITANCE,SAETHRE-CHOTZEN SYNDROME,SETLEIS SYNDROME,ATROPHIC SKIN,UNDIAGNOSED DISEASES,TRANSCRIPTION FACTOR,FRAMESHIFT MUTATION,FAMILIAL OCCURRENCE},
  language     = {eng},
  number       = {1},
  pages        = {99--110},
  title        = {Recurrent mutations in the basic domain of TWIST2 cause ablepharon macrostomia and Barber-Say syndromes},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2015.05.017},
  volume       = {97},
  year         = {2015},
}

Chicago
Marchegiani, Shannon, Taylor Davis, Federico Tessadori, Gijs van Haaften, Francesco Brancati, Alexander Hoischen, Haigen Huang, et al. 2015. “Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.” American Journal of Human Genetics 97 (1): 99–110.
APA
Marchegiani, S., Davis, T., Tessadori, F., van Haaften, G., Brancati, F., Hoischen, A., Huang, H., et al. (2015). Recurrent mutations in the basic domain of TWIST2 cause ablepharon macrostomia and Barber-Say syndromes. AMERICAN JOURNAL OF HUMAN GENETICS, 97(1), 99–110.
Vancouver
1.
Marchegiani S, Davis T, Tessadori F, van Haaften G, Brancati F, Hoischen A, et al. Recurrent mutations in the basic domain of TWIST2 cause ablepharon macrostomia and Barber-Say syndromes. AMERICAN JOURNAL OF HUMAN GENETICS. 2015;97(1):99–110.
MLA
Marchegiani, Shannon, Taylor Davis, Federico Tessadori, et al. “Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.” AMERICAN JOURNAL OF HUMAN GENETICS 97.1 (2015): 99–110. Print.