Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Nat Genet. 2013 Mar;45(3):304-7. doi: 10.1038/ng.2531. Epub 2013 Jan 27.
Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ∼1 in 2,200 (refs. 1,2). A specific genetic etiology can be identified in ∼21% of cases, including mutations of TWIST1, which encodes a class II basic helix-loop-helix (bHLH) transcription factor, and causes Saethre-Chotzen syndrome, typically associated with coronal synostosis. Using exome sequencing, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis. The mutations predominantly occurred in individuals with coronal synostosis and accounted for 32% and 10% of subjects with bilateral and unilateral pathology, respectively. TCF12 encodes one of three class I E proteins that heterodimerize with class II bHLH proteins such as TWIST1. We show that TCF12 and TWIST1 act synergistically in a transactivation assay and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 have severe coronal synostosis. Hence, the dosage of TCF12-TWIST1 heterodimers is critical for normal coronal suture development.
颅缝早闭是一种颅缝过早融合的异质性疾病，其患病率约为每 2200 例中有 1 例（参考文献 1,2）。约 21%的病例可确定特定的遗传病因，包括 TWIST1 基因突变，该基因编码一种 II 类碱性螺旋-环-螺旋（bHLH）转录因子，引起 Saethre-Chotzen 综合征，通常与冠状缝早闭有关。我们通过外显子组测序，在 347 个无亲缘关系的颅缝早闭患者样本中发现了 38 个杂合性 TCF12 突变。这些突变主要发生在冠状缝早闭患者中，分别占双侧和单侧病变患者的 32%和 10%。TCF12 编码三个 I 类 E 蛋白之一，与 TWIST1 等 II 类 bHLH 蛋白形成异二聚体。我们表明，在转激活测定中，TCF12 和 TWIST1 协同作用，并且 Tcf12 和 Twist1 双杂合功能丧失突变的小鼠有严重的冠状缝早闭。因此，TCF12-TWIST1 异二聚体的剂量对于正常冠状缝发育至关重要。
