Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis

• Published in: Nature genetics Vol. 45; no. 3; pp. 304 - 307
• Main Authors: Sharma, Vikram P, Fenwick, Aimée 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2013; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/208/737; 692/699/1670/1669; Acrocephalosyndactylia - complications; Acrocephalosyndactylia - genetics; Acrocephalosyndactylia - pathology; Agriculture; Animal Genetics and Genomics; Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Biomedical research; Biomedicine; Cancer Research; Cell culture; Confidence intervals; Cranial Sutures - growth & development; Cranial Sutures - pathology; Craniosynostoses; Craniosynostoses - complications; Craniosynostoses - genetics; Craniosynostoses - pathology; Dimerization; DNA sequencing; Exome; Gene Expression Regulation, Developmental; Gene Function; Gene mutations; Genetic aspects; Genomics; Genotype & phenotype; Heterozygote; Human Genetics; Humans; letter; Medical research; Mice; Mice, Transgenic; Molecular Sequence Data; Mutation; Nuclear Proteins - genetics; Nucleotide sequencing; Physiological aspects; Proteins; Sequence Analysis, DNA; Transcriptional Activation; Twist-Related Protein 1 - genetics; United Kingdom; Netherlands
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2531

Andrew Wilkie and colleagues report that mutations in TCF12 cause coronal craniosynostosis. They found heterozygous mutations in 38 unrelated families. 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 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 , 5 , 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.