Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Marchegiani, S., Davis, T., Tessadori, F., van Haaften, G., Brancati, F., Hoischen, A., Huang, H., Valkanas, E., Pusey, B., Schanze, D., Venselaar, H., Vulto-van Silfhout, A.T., Wolfe, L.A., Tifft, C.J., Zerfas, P.M., Zambruno, G., Kariminejad, A., Sabbagh-Kermani, F., Lee, J., Tsokos, M.G., Lee, C.R., Ferraz, V., da Silva, E.M., Stevens, C.A., Roche, N., Bartsch, O., Farndon, P., Bermejo-Sanchez, E., Brooks, B.P., Maduro, V., Dallapiccola, B., Ramos, F.J., Chung, H.B., Le Caignec, C., Martins, F., Jacyk, W.K., Mazzanti, L., Brunner, H.G., Bakkers, J., Lin, S., Malicdan, M.C., Boerkoel, C.F., Gahl, W.A., de Vries, B.B., van Haelst, M.M., Zenker, M., Markello, T.C.
American journal of human genetics   97(1): 99-110 (Journal)
Registered Authors
Bakkers, Jeroen, Brooks, Brian P., Huang, Haigen, Lin, Shuo
MeSH Terms
  • Abnormalities, Multiple/genetics*
  • Abnormalities, Multiple/pathology
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Chromatin Immunoprecipitation
  • Exome/genetics
  • Eye Abnormalities/genetics*
  • Eye Abnormalities/pathology
  • Eyelid Diseases/genetics*
  • Eyelid Diseases/pathology
  • HeLa Cells
  • Hirsutism/genetics*
  • Hirsutism/pathology
  • Humans
  • Hypertelorism/genetics*
  • Hypertelorism/pathology
  • Hypertrichosis/genetics*
  • Hypertrichosis/pathology
  • Macrostomia/genetics*
  • Macrostomia/pathology
  • Microscopy, Electron
  • Models, Molecular*
  • Molecular Sequence Data
  • Mutation, Missense/genetics
  • Phenotype*
  • Protein Conformation
  • Repressor Proteins/chemistry
  • Repressor Proteins/genetics*
  • Sequence Analysis, DNA
  • Skin Abnormalities/genetics*
  • Skin Abnormalities/pathology
  • Twist-Related Protein 1/chemistry
  • Twist-Related Protein 1/genetics*
  • Zebrafish
26119818 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes