title: Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia.
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.
authors.affiliation: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Gray
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Kannu
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
authors.forename: Swarkar
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
authors.forename: Christine
authors.initials: C
authors.lastname: Neyt
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
authors.forename: Dongping
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
authors.forename: Nandina
authors.initials: N
authors.lastname: Paria
authors.affiliation: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Daniel
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
authors.forename: Heather
authors.initials: H
authors.lastname: Whetstone
authors.affiliation: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Sprenger
authors.affiliation: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
authors.forename: Philipp
authors.initials: P
authors.lastname: Hammerschmidt
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Weng
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
authors.forename: Lucie
authors.initials: L
authors.lastname: Dupuis
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Jobling
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
authors.forename: Roberto
authors.initials: R
authors.lastname: Mendoza-Londono
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Dray
authors.affiliation: Department of Orthopaedic Surgery, First Affiliated Hospital and Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Peiqiang
authors.initials: P
authors.lastname: Su
authors.affiliation: Department of Anatomy, University of Otago, Dunedin 9016, New Zealand.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Wilson
authors.affiliation: Department of Laboratories, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Raj P
authors.initials: RP
authors.lastname: Kapur
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD 21231-2410, USA.
authors.forename: Edward F
authors.initials: EF
authors.lastname: McCarthy
authors.affiliation: Department of Surgery, University of Toronto, Toronto, ON M5G1X8, Canada.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Alman
authors.affiliation: Division of Orthopedics, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Howard
authors.affiliation: Division of Pathology, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, ON M5G1X8, Canada.
authors.forename: Gino R
authors.initials: GR
authors.lastname: Somers
authors.affiliation: 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.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: Department of Orthopedic Surgery, Starship Children's Hospital, Auckland 1023, New Zealand.
authors.forename: Simon
authors.initials: S
authors.lastname: Manners
authors.affiliation: UCL Cancer Institute, University College London, London WC1E6DD, Department of Histopathology, The Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
authors.affiliation: 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.
authors.forename: Karl E
authors.initials: KE
authors.lastname: Rathjen
authors.affiliation: 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.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Karol
authors.affiliation: Department of Orthopedic Surgery, Starship Children's Hospital, Auckland 1023, New Zealand.
authors.forename: Haemish
authors.initials: H
authors.lastname: Crawford
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
authors.forename: David M
authors.initials: DM
authors.lastname: Markie
authors.affiliation: 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.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Rios
authors.affiliation: 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.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wise
authors.affiliation: Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
mesh_terms: D000328:Adult; D001483:Base Sequence; D001848:Bone Diseases, Developmental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002648:Child; D005091:Exons; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005799:Genes, Dominant; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics*; D010375:Pedigree; D010521:Periosteum / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing
chemical_list: C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met