BoneKEy Reports | BoneKEy Watch
ERF, a new candidate gene in craniosynostosis may regulate osteogenesis
DOI:10.1038/bonekey.2013.98
DNA sequence analysis of a teenage boy with craniosynostosis, and of his immediate family, revealed a nonsense mutation within the gene that encodes ethylene response factor (ERF). Mutations within the same gene were detected in unrelated patients with craniosynostosis, which was characterized by synostosis at multiple suture sites, dysmorphism of the cranium and face, Chiari malformations (structural abnormalities in the cerebellum due to a restriction in space within the skull) and a delay in developing speech.
ERF had not previously been suspected as having a role in craniosynostosis or in osteogenesis. However, ERF is known to code for an inhibitory transcription factor that binds extracellular signal-related kinases 1 and 2 (ERK1/2), which play an important role in RAS-MEK-ERK signal transduction. Some cases of craniosynostosis had previously been associated with activation of ERK1/2 signaling.
Mice engineered to have reduced Erf transcription (down 29% compared with wild type) developed domed heads by the time they were 6 weeks old; craniosynostosis was detected using microCT scanning, which revealed that multiple calvarial sutures were affected. Studies using embryonic fibroblasts from the engineered mice showed that preferential ERF binding occurs away from RUNX or AP-1 promoters and suggested that ERF may act through the RAS-ERK signaling pathway.
Editor’s comment: Last month, a genome wide association study of nonsyndromic sagittal craniosynostosis suggested susceptibility loci near BMP2 and within BBS9. This new study now identifies a mutation in ERF as a cause of a newly identified type of complex craniosynostosis and suggests that ERF could be a previously unrecognized regulator of osteogenic stimulation.
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