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

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.
AuthorsBeth A Firulli, Dayana Krawchuk, Victoria E Centonze, Neil Vargesson, David M Virshup, Simon J Conway, Peter Cserjesi, Ed Laufer, Anthony B Firulli
JournalNature genetics (Nat Genet) Vol. 37 Issue 4 Pg. 373-81 (Apr 2005) ISSN: 1061-4036 [Print] United States
PMID15735646 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Basic Helix-Loop-Helix Transcription Factors
  • HAND2 protein, human
  • Hand2 protein, mouse
  • Nuclear Proteins
  • TWIST1 protein, human
  • Transcription Factors
  • Twist Transcription Factor
  • Zebrafish Proteins
  • hand2 protein, zebrafish
  • Cyclic AMP-Dependent Protein Kinases
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2
  • Acrocephalosyndactylia (genetics, metabolism, pathology)
  • Amino Acid Sequence
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Chick Embryo (virology)
  • Chickens
  • Conserved Sequence
  • Cyclic AMP-Dependent Protein Kinases (pharmacology)
  • Dimerization
  • Helix-Loop-Helix Motifs
  • Hindlimb (abnormalities)
  • Humans
  • Kidney (metabolism)
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutation (genetics)
  • Nuclear Proteins (genetics, physiology)
  • Phenotype
  • Phosphoprotein Phosphatases (pharmacology)
  • Phosphorylation (drug effects)
  • Protein Phosphatase 2
  • Sequence Homology, Amino Acid
  • Transcription Factors (genetics, physiology)
  • Twist Transcription Factor
  • Zebrafish Proteins

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