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

Nat Genet. 2005 Apr;37(4):373-81. doi: 10.1038/ng1525. Epub 2005 Feb 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acrocephalosyndactylia / genetics
  • Acrocephalosyndactylia / metabolism*
  • Acrocephalosyndactylia / 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
  • Nuclear Proteins / physiology*
  • Phenotype
  • Phosphoprotein Phosphatases / pharmacology
  • Phosphorylation / drug effects
  • Protein Phosphatase 2
  • Sequence Homology, Amino Acid
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Twist-Related Protein 1
  • Zebrafish Proteins

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • HAND2 protein, human
  • Hand2 protein, mouse
  • Nuclear Proteins
  • TWIST1 protein, human
  • Transcription Factors
  • Twist-Related Protein 1
  • Zebrafish Proteins
  • hand2 protein, zebrafish
  • Cyclic AMP-Dependent Protein Kinases
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2

Associated data

  • GENBANK/AF093816
  • GENBANK/AF172286
  • GENBANK/AF205258
  • GENBANK/AF205259
  • GENBANK/AF228334
  • GENBANK/AF266260
  • GENBANK/AF517121
  • GENBANK/AJ131110
  • GENBANK/M63649
  • GENBANK/S78079
  • GENBANK/S79216
  • GENBANK/U18658
  • GENBANK/U36384
  • GENBANK/U40039
  • GENBANK/U40040
  • GENBANK/U40041
  • GENBANK/U72641
  • GENBANK/U80998
  • GENBANK/X14569
  • RefSeq/NM_057179
  • RefSeq/NM_204084
  • RefSeq/NP_509367