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Article: Recurrent mutations in the basic domain of TWIST2 cause Ablepharon Macrostomia syndrome and Barber-Say syndrome

TitleRecurrent mutations in the basic domain of TWIST2 cause Ablepharon Macrostomia syndrome and Barber-Say syndrome
Authors
Issue Date2015
PublisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/
Citation
American Journal of Human Genetics, 2015, v. 97 n. 1, p. 99-110 How to Cite?
AbstractAblepharon 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. TWIST2 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-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/211874
ISSN
2015 Impact Factor: 10.794
2015 SCImago Journal Rankings: 8.769

 

DC FieldValueLanguage
dc.contributor.authorMarchegiani, S-
dc.contributor.authorDavis, T-
dc.contributor.authorTessadori, F-
dc.contributor.authorvan Haaften, G-
dc.contributor.authorBrancati, F-
dc.contributor.authorHoischen, H-
dc.contributor.authorHuang, H-
dc.contributor.authorValkanas, E-
dc.contributor.authorPusey, B-
dc.contributor.authorSchanze, D-
dc.contributor.authorVenselaaar, H-
dc.contributor.authorVulto-van Silfhourt, AT-
dc.contributor.authorWolfe, LA-
dc.contributor.authorTifft, CJ-
dc.contributor.authorZerfas, PM-
dc.contributor.authorZambruno, G-
dc.contributor.authorKariminejad, A-
dc.contributor.authorKermani, FS-
dc.contributor.authorLee, J-
dc.contributor.authorTsokos, MG-
dc.contributor.authorLee, CCR-
dc.contributor.authorFerraz, V-
dc.contributor.authorda Silva, EM-
dc.contributor.authorStevens, CA-
dc.contributor.authorRoche, N-
dc.contributor.authorBartsch, O-
dc.contributor.authorFarndon, P-
dc.contributor.authorBermejo-Sanchez, E-
dc.contributor.authorBrooks, BP-
dc.contributor.authorMaduro, V-
dc.contributor.authorDallapiccola, B-
dc.contributor.authorRamos, FJ-
dc.contributor.authorChung, BHY-
dc.contributor.authorCaignec, CL-
dc.contributor.authorMartins, F-
dc.contributor.authorJacyk, WK-
dc.contributor.authorMazzanti, L-
dc.contributor.authorBrunner, HG-
dc.contributor.authorBakkers, J-
dc.contributor.authorLin, S-
dc.contributor.authorMalicdan, MCV-
dc.contributor.authorBoerkoel, CF-
dc.contributor.authorGahl, WA-
dc.contributor.authorde Vries, BBA-
dc.contributor.authorvan Haelst, MM-
dc.contributor.authorZenker, M-
dc.contributor.authorMarkello, T-
dc.date.accessioned2015-07-21T02:14:30Z-
dc.date.available2015-07-21T02:14:30Z-
dc.date.issued2015-
dc.identifier.citationAmerican Journal of Human Genetics, 2015, v. 97 n. 1, p. 99-110-
dc.identifier.issn0002-9297-
dc.identifier.urihttp://hdl.handle.net/10722/211874-
dc.description.abstractAblepharon 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. TWIST2 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-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.-
dc.languageeng-
dc.publisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/-
dc.relation.ispartofAmerican Journal of Human Genetics-
dc.titleRecurrent mutations in the basic domain of TWIST2 cause Ablepharon Macrostomia syndrome and Barber-Say syndrome-
dc.typeArticle-
dc.identifier.emailChung, BHY: bhychung@hku.hk-
dc.identifier.authorityChung, BHY=rp00473-
dc.identifier.doi10.1016/j.ajhg.2015.05.017-
dc.identifier.pmid26119818-
dc.identifier.hkuros244456-
dc.identifier.volume97-
dc.identifier.issue1-
dc.identifier.spage99-
dc.identifier.epage110-
dc.publisher.placeUnited States-

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