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