2. Academic Validation
  3. Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia

Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia

  • Am J Hum Genet. 2015 Dec 3;97(6):837-47. doi: 10.1016/j.ajhg.2015.11.001.
Mary J Gray 1,  Peter Kannu 2,  Swarkar Sharma 3,  Christine Neyt 1,  Dongping Zhang 3,  Nandina Paria 3,  Philip B Daniel 1,  Heather Whetstone 4,  Hans-Georg Sprenger 1,  Philipp Hammerschmidt 1,  Angela Weng 4,  Lucie Dupuis 5,  Rebekah Jobling 5,  Roberto Mendoza-Londono 5,  Michael Dray 6,  Peiqiang Su 7,  Megan J Wilson 8,  Raj P Kapur 9,  Edward F McCarthy 10,  Benjamin A Alman 11,  Andrew Howard 12,  Gino R Somers 13,  Christian R Marshall 14,  Simon Manners 15,  Adrienne M Flanagan 16,  Karl E Rathjen 17,  Lori A Karol 17,  Haemish Crawford 15,  David M Markie 18,  Jonathan J Rios 19,  Carol A Wise 20,  Stephen P Robertson 1
Affiliations

Affiliations

  • 1 Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
  • 2 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada. Electronic address: peter.kannu@sickkids.ca.
  • 3 Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
  • 4 Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
  • 5 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
  • 6 Department of Pathology, Middlemore Hospital, Auckland 2025, New Zealand; Bone & Joint Research Group, Department of Medicine, University of Auckland, Auckland 1142, New Zealand; Histology Department, Waikato Hospital, Hamilton 3240, New Zealand.
  • 7 Department of Orthopaedic Surgery, First Affiliated Hospital and Sun Yat-Sen University, Guangzhou 510080, China.
  • 8 Department of Anatomy, University of Otago, Dunedin 9016, New Zealand.
  • 9 Department of Laboratories, Seattle Children's Hospital, Seattle, WA 98105, USA.
  • 10 Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD 21231-2410, USA.
  • 11 Department of Surgery, University of Toronto, Toronto, ON M5G1X8, Canada.
  • 12 Division of Orthopedics, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
  • 13 Division of Pathology, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
  • 14 The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
  • 15 Department of Orthopedic Surgery, Starship Children's Hospital, Auckland 1023, New Zealand.
  • 16 UCL Cancer Institute, University College London, London WC1E6DD, Department of Histopathology, The Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK.
  • 17 Department of Orthopedics, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75350, USA.
  • 18 Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
  • 19 Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75350, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75350, USA; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75350, USA.
  • 20 Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75350, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75350, USA; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75350, USA. Electronic address: carol.wise@tsrh.org.
PMID: 26637977 DOI: 10.1016/j.ajhg.2015.11.001
Abstract

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.

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