Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities

Beth A. Firulli, Dayana Krawchuk, Victoria E Centonze, Neil Vargesson, David M Virshup, Simon J Conway, Peter Cserjesi, Ed Laufer (Corresponding Author), Anthony B Firulli (Corresponding Author)

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126 Citations (Scopus)

Abstract

Autosomal dominant mutations in the gene encoding the basic helix-loop-helix transcription factor Twist1 are associated with limb and craniofacial defects in humans with Saethre-Chotzen syndrome. The molecular mechanism underlying these phenotypes is poorly understood. We show that ectopic expression of the related basic helix-loop-helix factor Hand2 phenocopies Twist1 loss of function in the limb and that the two factors have a gene dosage - dependent antagonistic interaction. Dimerization partner choice by Twist1 and Hand2 can be modulated by protein kinase A - and protein phosphatase 2A - regulated phosphorylation of conserved helix I residues. Notably, multiple Twist1 mutations associated with Saethre-Chotzen syndrome alter protein kinase A - mediated phosphorylation of Twist1, suggesting that misregulation of Twist1 dimerization through either stoichiometric or post-translational mechanisms underlies phenotypes of individuals with Saethre-Chotzen syndrome.

Original languageEnglish
Pages (from-to)373-381
Number of pages8
JournalNature Genetics
Volume37
Issue number4
Early online date27 Feb 2005
DOIs
Publication statusPublished - Apr 2005

Keywords

  • BHLH TRANSCRIPTION FACTOR
  • OSTEOBLAST DIFFERENTIATION
  • BASIC DOMAIN
  • DNA-BINDING
  • CHICK LIMB
  • MUTATIONS
  • PROTEIN
  • HEDGEHOG
  • DHAND
  • GENE

Cite this

Firulli, B. A., Krawchuk, D., Centonze, V. E., Vargesson, N., Virshup, D. M., Conway, S. J., Cserjesi, P., Laufer, E., & Firulli, A. B. (2005). Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities. Nature Genetics, 37(4), 373-381. https://doi.org/10.1038/NG1525