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

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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.
Keywords
EPITHELIAL-MESENCHYMAL TRANSITION, MORPHOLOGY STANDARD TERMINOLOGY, AUTOSOMAL-DOMINANT INHERITANCE, SAETHRE-CHOTZEN SYNDROME, SETLEIS SYNDROME, ATROPHIC SKIN, UNDIAGNOSED DISEASES, TRANSCRIPTION FACTOR, FRAMESHIFT MUTATION, FAMILIAL OCCURRENCE

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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.
@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},
}

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