Firulli Beth A, Krawchuk Dayana, Centonze Victoria E, Vargesson Neil, Virshup David M, Conway Simon J, Cserjesi Peter, Laufer Ed, Firulli Anthony B
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.
Nat Genet. 2005 Apr;37(4):373-81. doi: 10.1038/ng1525. Epub 2005 Feb 27.
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.
编码碱性螺旋-环-螺旋转录因子Twist1的基因中的常染色体显性突变与患有塞特雷-乔岑综合征的人类的肢体和颅面缺陷相关。这些表型背后的分子机制尚不清楚。我们发现，相关碱性螺旋-环-螺旋因子Hand2的异位表达模拟了肢体中Twist1功能丧失的情况，并且这两个因子具有基因剂量依赖性拮抗相互作用。Twist1和Hand2的二聚化伙伴选择可通过蛋白激酶A和蛋白磷酸酶2A调节的保守螺旋I残基的磷酸化来调节。值得注意的是，与塞特雷-乔岑综合征相关的多个Twist1突变改变了蛋白激酶A介导的Twist1磷酸化，这表明通过化学计量或翻译后机制对Twist1二聚化的错误调节是塞特雷-乔岑综合征患者表型的基础。
