title: 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.affiliation: Wells Center for Pediatric Research, James Whitcomb Riley Hospital for Children, Department of Pediatrics, Indiana Medical School, 1044 W. Walnut R4 371, Indianapolis, Indiana 46202-5225, USA. tfirulli@iupui.edu
authors.forename: Beth A
authors.initials: BA
authors.lastname: Firulli
authors.forename: Dayana
authors.initials: D
authors.lastname: Krawchuk
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Centonze
authors.forename: Neil
authors.initials: N
authors.lastname: Vargesson
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Peter
authors.initials: P
authors.lastname: Cserjesi
authors.forename: Ed
authors.initials: E
authors.lastname: Laufer
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Firulli
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002642:Chick Embryo / Q000821:virology; D002645:Chickens; D017124:Conserved Sequence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D019281:Dimerization; D018257:Helix-Loop-Helix Motifs; D006614:Hindlimb / Q000002:abnormalities*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D010749:Phosphoprotein Phosphatases / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D051879:Twist-Related Protein 1; D029961:Zebrafish Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D029961:Zebrafish Proteins; C498765:HAND2 protein, human; C498766:Hand2 protein, mouse; C103173:TWIST1 protein, human; C410915:hand2 protein, zebrafish
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