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RESEARCH PRODUCT
Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes
Elise ValkanasHon-yin Brian ChungPeter FarndonPatricia M. ZerfasOliver BartschMartin ZenkerJeroen BakkersAlexander HoischenFeliciano J. RamosEva Bermejo-sánchezHaigen HuangGijs Van HaaftenLynne A. WolfeTaylor DavisEduarda Morgana Da SilvaHan G. BrunnerW. K. JacykBruno DallapiccolaLaura MazzantiCathy A. StevensMieke M. Van HaelstHanka VenselaarCornelius F. BoerkoelFrancesco BrancatiCynthia J. TifftMay Christine V. MalicdanNathalie RocheBert B.a. De VriesVictor Evangelista De Faria FerrazChyi-chia Richard LeeBrian P. BrooksFarahnaz Sabbagh-kermaniFederico TessadoriDenny SchanzeBarbara N. PuseyAriana KariminejadValerie MaduroJanice LeeGiovanna ZambrunoShuo LinCédric Le CaignecThomas C. MarkelloMaria TsokosShannon MarchegianiFabiana MartinsWilliam A. GahlAnneke T. Vulto-van Silfhoutsubject
Models MolecularCandidate geneHirsutismProtein ConformationHeLa Cellmedicine.disease_causeTranscriptomeTwist transcription factorModelsGenetics(clinical)ExomeEye AbnormalitiesNon-U.S. Gov'tExomeGenetics (clinical)ZebrafishGeneticsMutationMicroscopyMacrostomiaSetleis syndromeHypertelorismResearch Support Non-U.S. Gov'tHypertrichosiEyelid DiseaseGENÉTICAPhenotypeEyelid DiseasesAbnormalitiesMultipleSequence AnalysisHumanChromatin ImmunoprecipitationMolecular Sequence DataMutation MissenseHypertrichosisAbnormalities; Multiple; Amino Acid Sequence; Animals; Base Sequence; Chromatin Immunoprecipitation; Exome; Eye Abnormalities; Eyelid Diseases; HeLa Cells; Hirsutism; Humans; Hypertelorism; Hypertrichosis; Macrostomia; Microscopy; Electron; Molecular Sequence Data; Mutation; Missense; Protein Conformation; Repressor Proteins; Sequence Analysis; DNA; Skin Abnormalities; Twist Transcription Factor; Zebrafish; Models; Molecular; Phenotype; Genetics; Genetics (clinical)Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0]BiologyResearch SupportElectronArticleFrameshift mutationGeneticAblepharon macrostomia syndromeSkin AbnormalitieGeneticsmedicineJournal ArticleAnimalsHumansAbnormalities MultipleAmino Acid SequenceNeurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]Base SequenceAnimalTwist-Related Protein 1MolecularSequence Analysis DNADNARepressor Proteinmedicine.diseaseRepressor ProteinsTwist Transcription FactorEye AbnormalitieMicroscopy ElectronMutationSkin Abnormalitiessense organsMissenseNanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]HeLa Cellsdescription
Contains fulltext : 153827.pdf (Publisher’s version ) (Open Access) 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. 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-07-02 | American journal of human genetics |