Background Osteofibrous dysplasia (OFD) is a proliferative fibro-osseous condition affecting bone with an onset in early childhood. Affected individuals develop tibial bowing and spontaneous non-healing fractures.

Objectives The purpose of this study was to identify the genetic cause of OFD and clarify how the mutation causes the phenotype.

Design/methods Exome sequencing was performed on individuals diagnosed with bilateral OFD. Cell culture and mouse studies were utilised to study disease mechanism.

Results We identified mutations in a gene encoding a receptor tyrosine kinase, in three families segregating an autosomal dominant form of OFD and in a fourth sporadic case. All mutations abolished the splice inclusion of an exon in transcripts resulting in receptors lacking a juxtamembrane cytoplasmic domain. Our mouse data indicate that exclusion of this domain is a physiologically regulated event in the periosteum, which is spatially partitioned during development. Abnormal fibro-osseous bone cells from the patient tibial fracture site were compared to the cells obtained from unaffected proximal tibial bone. When cultured in osteogenic differentiation media, fracture site-derived osteoblasts displayed considerably higher levels of mineralization compared to the cells from the unaffected tibial bone. Moreover, the fracture site osteoblasts proliferated more rapidly compared to the control cells. Mutant osteoclasts showed decreased bone resorption.

Conclusions Together these data indicate that the production of this mutant receptor isoform is a developmentally regulated event during mammalian embryonic development and mutations which render this alternative splice event constitutional subvert core functions of this receptor that regulate osteogenic functions within the periosteum.