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

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.

• Authors: Beth A Firulli, Dayana Krawchuk, Victoria E Centonze, Neil Vargesson, David M Virshup, Simon J Conway, Peter Cserjesi, Ed Laufer, Anthony B Firulli
• Journal: Nature genetics (Nat Genet) Vol. 37 Issue 4 Pg. 373-81 (Apr 2005) ISSN: 1061-4036 [Print] United States
• PMID: 15735646 (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-Related Protein 1
• Zebrafish Proteins
• hand2 protein, zebrafish
• Cyclic AMP-Dependent Protein Kinases
• Phosphoprotein Phosphatases
• Protein Phosphatase 2

Topics

• 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-Related Protein 1
• Zebrafish Proteins