期刊
NATURE GENETICS
卷 45, 期 3, 页码 304-307出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2531
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资金
- National Institute for Health Research (NIHR) Biomedical Research Centre Oxford
- Oxford University Clinical Academic Graduate School
- Oxfordshire Health Services Research Committee
- Oxford Craniofacial Unit Charitable Fund
- Thames Valley Comprehensive Local Research Network
- Dutch Center for Translational Molecular Medicine
- Carolien Bijl Foundation
- US National Institutes of Health (NIH) [R01DE016320, R01DE019650]
- Wellcome Trust [093329]
- MRC [MC_UU_12010/6] Funding Source: UKRI
- Medical Research Council [MC_UU_12010/6] Funding Source: researchfish
Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of similar to 1 in 2,200 (refs. 1,2). A specific genetic etiology can be identified in similar to 21% of cases(3), 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(4-6). 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.
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