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 Conway, Peter Cserjesi, Ed Laufer, Anthony Firulli

Research output: Contribution to journalArticle

124 Citations (Scopus)

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
Pages (from-to)373-381
Number of pages9
JournalNature Genetics
Volume37
Issue number4
DOIs
StatePublished - Apr 2005

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Acrocephalosyndactylia
Dimerization
Extremities
Cyclic AMP-Dependent Protein Kinases
Phosphorylation
Basic Helix-Loop-Helix Transcription Factors
Phenotype
Protein Phosphatase 2
Mutation
Gene Dosage
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities. / Firulli, Beth A.; Krawchuk, Dayana; Centonze, Victoria E.; Vargesson, Neil; Virshup, David M.; Conway, Simon; Cserjesi, Peter; Laufer, Ed; Firulli, Anthony.

In: Nature Genetics, Vol. 37, No. 4, 04.2005, p. 373-381.

Research output: Contribution to journalArticle

Firulli, BA, Krawchuk, D, Centonze, VE, Vargesson, N, Virshup, DM, Conway, S, Cserjesi, P, Laufer, E & Firulli, A 2005, 'Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities', Nature Genetics, vol. 37, no. 4, pp. 373-381. https://doi.org/10.1038/ng1525
Firulli, Beth A. ; Krawchuk, Dayana ; Centonze, Victoria E. ; Vargesson, Neil ; Virshup, David M. ; Conway, Simon ; Cserjesi, Peter ; Laufer, Ed ; Firulli, Anthony. / Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities. In: Nature Genetics. 2005 ; Vol. 37, No. 4. pp. 373-381.
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