Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis.
Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis.
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DOI：
10.1038/ng.2531
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发表时间：
2013-03
期刊：
影响因子：
30.8
通讯作者：
Wilkie, Andrew O. M.
中科院分区：
文献类型：
--
作者：
Sharma, Vikram P.;Fenwick, Aimee L.;Brockop, Mia S.;McGowan, Simon J.;Goos, Jacqueline A. C.;Hoogeboom, A. Jeannette M.;Brady, Angela F.;Jeelani, Nu Owase;Lynch, Sally Ann;Mulliken, John B.;Murray, Dylan J.;Phipps, Julie M.;Sweeney, Elizabeth;Tomkins, Susan E.;Wilson, Louise C.;Bennett, Sophia;Cornall, Richard J.;Broxholme, John;Kanapin, Alexander;Johnson, David;Wall, Steven A.;van der Spek, Peter J.;Mathijssen, Irene M. J.;Maxson, Robert E.;Twigg, Stephen R. F.;Wilkie, Andrew O. M.
颅缝早闭，即颅缝过早融合，是一种异质性疾病，患病率约为1/2200（参考文献）。在约21%的病例中可以确定特定的遗传病因，包括TWIST 1的突变，TWIST 1编码II类碱性螺旋-环-螺旋（bHLH）转录因子，并导致Saethre-Chotzen综合征，通常与冠状骨结合有关。从外显子组测序筛选开始，我们在347个无关的颅缝早闭患者样本中发现了38个杂合TCF 12突变。这些突变主要发生在冠状骨结合的患者中，分别占双侧和单侧病变受试者的32%和10%。TCF 12编码三种I类E蛋白之一，其与II类bHLH蛋白如TWIST 1异源二聚化。我们发现，TCF 12和TWIST 1协同作用的反式激活试验，和小鼠双杂合Tcf 12和Twist 1的功能丧失突变表现出严重的冠状骨结合。因此，TCF 12/TWIST 1异源二聚体的剂量对于冠状缝发育至关重要。
Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ~1 in 2,200 (refs.). 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. Starting with an exome sequencing screen, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis. The mutations predominantly occurred in patients 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 exhibit severe coronal synostosis. Hence, the dosage of TCF12/TWIST1 heterodimers is critical for coronal suture development.
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