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

Beth A. Firulli, Dayana Krawchuk, Victoria E. Centonze, Neil Vargesson, David M. Virshup, Simon J. Conway, Peter Cserjesi, Ed Laufer, Anthony B. Firulli

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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 languageEnglish (US)
Pages (from-to)373-381
Number of pages9
JournalNature genetics
Volume37
Issue number4
DOIs
StatePublished - Apr 1 2005

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ASJC Scopus subject areas

  • Genetics

Cite this

Firulli, B. A., Krawchuk, D., Centonze, V. E., Vargesson, N., Virshup, D. M., Conway, S. J., Cserjesi, P., Laufer, E., & Firulli, A. B. (2005). Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities. Nature genetics, 37(4), 373-381. https://doi.org/10.1038/ng1525