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Further insights into the genetic basis of craniosynostosis



DOI:10.1038/bonekey.2013.85

Sharma et al. used exome sequencing to examine 347 samples from people with craniosynostosis to further elucidate the genetic basis of this complex condition.

They identified 38 heterozygous mutations in the TCF12 gene, which codes for one of the class I E proteins, which form heterodimers with class II basic helix-loop-helix (bHLH) transcription factors, such as TWIST1. Mutations in TWIST1 are known to be associated with Saethre–Chotzen syndrome, which is often characterized by coronal synostosis.

To test their hypothesis that TCF12 haploinsufficiency leads to coronal synostosis, the authors then compared different strains of mice, one with a mutation in Tcf12, one with a mutation in Twist1 and a third with both mutations. At three weeks old, the first strain had normal coronal sutures, the second showed variable coronal synostosis and the third had severe coronal synostosis. The conclusion is that both gene products interact, probably forming a heterodimer, which then regulates development at the boundary of the cephalic mesoderm and the neural crest.

Editor’s comment: This work, together with a recent paper by Twigg et al., identify two new genetic causes of craniosynostosis. The transcription factors TCF12 and ethylene response factor both repress RUNX transcriptional activity, and mutations in genes encoding these factors can increase RUNX activity, resulting in enhanced osteogenesis at the cranial suture. These findings will contribute to clinical diagnosis and should also further clarify the causes of unexplained craniosynostosis.


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