Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia

Mary J. Gray, Peter Kannu, Swarkar Sharma, Christine Neyt, Dongping Zhang, Nandina Paria, Philip B. Daniel, Heather Whetstone, Hans Georg Sprenger, Philipp Hammerschmidt, Angela Weng, Lucie Dupuis, Rebekah Jobling, Roberto Mendoza-Londono, Michael Dray, Peiqiang Su, Megan J. Wilson, Raj P. Kapur, Edward F. McCarthy, Benjamin A. AlmanAndrew Howard, Gino R. Somers, Christian R. Marshall, Simon Manners, Adrienne M. Flanagan, Karl E. Rathjen, Lori A. Karol, Haemish Crawford, David M. Markie, Jonathan J. Rios, Carol A. Wise, Stephen P. Robertson

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


The periosteum contributes to bone repair and maintenance of cortical bone mass. In contrast to the understanding of bone development within the epiphyseal growth plate, factors that regulate periosteal osteogenesis have not been studied as intensively. Osteofibrous dysplasia (OFD) is a congenital disorder of osteogenesis and is typically sporadic and characterized by radiolucent lesions affecting the cortical bone immediately under the periosteum of the tibia and fibula. We identified germline mutations in MET, encoding a receptor tyrosine kinase, that segregate with an autosomal-dominant form of OFD in three families and a mutation in a fourth affected subject from a simplex family and with bilateral disease. Mutations identified in all families with dominant inheritance and in the one simplex subject with bilateral disease abolished the splice inclusion of exon 14 in MET transcripts, which resulted in a MET receptor (METΔ14) lacking a cytoplasmic juxtamembrane domain. Splice exclusion of this domain occurs during normal embryonic development, and forced induction of this exon-exclusion event retarded osteoblastic differentiation in vitro and inhibited bone-matrix mineralization. In an additional subject with unilateral OFD, we identified a somatic MET mutation, also affecting exon 14, that substituted a tyrosine residue critical for MET receptor turnover and, as in the case of the METΔ14 mutations, had a stabilizing effect on the mature protein. Taken together, these data show that aberrant MET regulation via the juxtamembrane domain subverts core MET receptor functions that regulate osteogenesis within cortical diaphyseal bone.

Original languageEnglish (US)
Pages (from-to)837-847
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number6
StatePublished - Dec 3 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia'. Together they form a unique fingerprint.

Cite this