The extracellular signal-related kinases 1 and 2 (ERK1/2) are key proteins 
mediating mitogen-activated protein kinase signaling downstream of RAS: 
phosphorylation of ERK1/2 leads to nuclear uptake and modulation of multiple 
targets. Here, we show that reduced dosage of ERF, which encodes an inhibitory 
ETS transcription factor directly bound by ERK1/2 (refs. 2,3,4,5,6,7), causes 
complex craniosynostosis (premature fusion of the cranial sutures) in humans and 
mice. Features of this newly recognized clinical disorder include 
multiple-suture synostosis, craniofacial dysmorphism, Chiari malformation and 
language delay. Mice with functional Erf levels reduced to ∼30% of normal 
exhibit postnatal multiple-suture synostosis; by contrast, embryonic calvarial 
development appears mildly delayed. Using chromatin immunoprecipitation in mouse 
embryonic fibroblasts and high-throughput sequencing, we find that ERF binds 
preferentially to elements away from promoters that contain RUNX or AP-1 motifs. 
This work identifies ERF as a novel regulator of osteogenic stimulation by 
RAS-ERK signaling, potentially by competing with activating ETS factors in 
multifactor transcriptional complexes.