TY - JOUR
T1 - Mutations Preventing Regulated Exon Skipping in MET Cause Osteofibrous Dysplasia
AU - Gray, Mary J.
AU - Kannu, Peter
AU - Sharma, Swarkar
AU - Neyt, Christine
AU - Zhang, Dongping
AU - Paria, Nandina
AU - Daniel, Philip B.
AU - Whetstone, Heather
AU - Sprenger, Hans Georg
AU - Hammerschmidt, Philipp
AU - Weng, Angela
AU - Dupuis, Lucie
AU - Jobling, Rebekah
AU - Mendoza-Londono, Roberto
AU - Dray, Michael
AU - Su, Peiqiang
AU - Wilson, Megan J.
AU - Kapur, Raj P.
AU - McCarthy, Edward F.
AU - Alman, Benjamin A.
AU - Howard, Andrew
AU - Somers, Gino R.
AU - Marshall, Christian R.
AU - Manners, Simon
AU - Flanagan, Adrienne M.
AU - Rathjen, Karl E.
AU - Karol, Lori A.
AU - Crawford, Haemish
AU - Markie, David M.
AU - Rios, Jonathan J.
AU - Wise, Carol A.
AU - Robertson, Stephen P.
N1 - Publisher Copyright:
© 2015 The American Society of Human Genetics.
PY - 2015/12/3
Y1 - 2015/12/3
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2015.11.001
DO - 10.1016/j.ajhg.2015.11.001
M3 - Article
C2 - 26637977
AN - SCOPUS:84951826019
SN - 0002-9297
VL - 97
SP - 837
EP - 847
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -