Skip to main content
Journal cover image

Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.

Publication ,  Journal Article
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 ...
Published in: Am J Hum Genet
December 3, 2015

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

December 3, 2015

Volume

97

Issue

6

Start / End Page

837 / 847

Location

United States

Related Subject Headings

  • RNA Splicing
  • Proto-Oncogene Proteins c-met
  • Protein Structure, Tertiary
  • Primary Cell Culture
  • Periosteum
  • Pedigree
  • Osteogenesis
  • Osteoblasts
  • Molecular Sequence Data
  • Middle Aged
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Gray, M. J., Kannu, P., Sharma, S., Neyt, C., Zhang, D., Paria, N., … Robertson, S. P. (2015). Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia. Am J Hum Genet, 97(6), 837–847. https://doi.org/10.1016/j.ajhg.2015.11.001
Gray, Mary J., Peter Kannu, Swarkar Sharma, Christine Neyt, Dongping Zhang, Nandina Paria, Philip B. Daniel, et al. “Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.Am J Hum Genet 97, no. 6 (December 3, 2015): 837–47. https://doi.org/10.1016/j.ajhg.2015.11.001.
Gray MJ, Kannu P, Sharma S, Neyt C, Zhang D, Paria N, et al. Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia. Am J Hum Genet. 2015 Dec 3;97(6):837–47.
Gray, Mary J., et al. “Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.Am J Hum Genet, vol. 97, no. 6, Dec. 2015, pp. 837–47. Pubmed, doi:10.1016/j.ajhg.2015.11.001.
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. Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia. Am J Hum Genet. 2015 Dec 3;97(6):837–847.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

December 3, 2015

Volume

97

Issue

6

Start / End Page

837 / 847

Location

United States

Related Subject Headings

  • RNA Splicing
  • Proto-Oncogene Proteins c-met
  • Protein Structure, Tertiary
  • Primary Cell Culture
  • Periosteum
  • Pedigree
  • Osteogenesis
  • Osteoblasts
  • Molecular Sequence Data
  • Middle Aged