Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.

Journal Article (Journal Article)

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 (MET(Δ14)) 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 MET(Δ14) 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.

Full Text

Duke Authors

Cited Authors

  • Gray, MJ; Kannu, P; Sharma, S; Neyt, C; Zhang, D; Paria, N; Daniel, PB; Whetstone, H; Sprenger, H-G; Hammerschmidt, P; Weng, A; Dupuis, L; Jobling, R; Mendoza-Londono, R; Dray, M; Su, P; Wilson, MJ; Kapur, RP; McCarthy, EF; Alman, BA; Howard, A; Somers, GR; Marshall, CR; Manners, S; Flanagan, AM; Rathjen, KE; Karol, LA; Crawford, H; Markie, DM; Rios, JJ; Wise, CA; Robertson, SP

Published Date

  • December 3, 2015

Published In

Volume / Issue

  • 97 / 6

Start / End Page

  • 837 - 847

PubMed ID

  • 26637977

Pubmed Central ID

  • PMC4678433

Electronic International Standard Serial Number (EISSN)

  • 1537-6605

Digital Object Identifier (DOI)

  • 10.1016/j.ajhg.2015.11.001


  • eng

Conference Location

  • United States