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 language | English |
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Pages (from-to) | 373-381 |
Number of pages | 8 |
Journal | Nature Genetics |
Volume | 37 |
Issue number | 4 |
Early online date | 27 Feb 2005 |
DOIs | |
Publication status | Published - Apr 2005 |
Keywords
- BHLH TRANSCRIPTION FACTOR
- OSTEOBLAST DIFFERENTIATION
- BASIC DOMAIN
- DNA-BINDING
- CHICK LIMB
- MUTATIONS
- PROTEIN
- HEDGEHOG
- DHAND
- GENE