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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Firulli, BA; Krawchuk, D; Centonze, VE; Vargesson, N; Virshup, DM; Conway, SJ; Cserjesi, P; Laufer, E; Firulli, AB

Published Date

  • April 2005

Published In

Volume / Issue

  • 37 / 4

Start / End Page

  • 373 - 381

PubMed ID

  • 15735646

Pubmed Central ID

  • 15735646

International Standard Serial Number (ISSN)

  • 1061-4036

Digital Object Identifier (DOI)

  • 10.1038/ng1525

Language

  • eng

Conference Location

  • United States