Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia.

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Version: author
Serval ID
serval:BIB_CD2DAF16D086
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia.
Journal
American journal of human genetics
Author(s)
Wade E.M., Daniel P.B., Jenkins Z.A., McInerney-Leo A., Leo P., Morgan T., Addor M.C., Adès L.C., Bertola D., Bohring A., Carter E., Cho T.J., Duba H.C., Fletcher E., Kim C.A., Krakow D., Morava E., Neuhann T., Superti-Furga A., Veenstra-Knol I., Wieczorek D., Wilson L.C., Hennekam R.C., Sutherland-Smith A.J., Strom T.M., Wilkie A.O., Brown M.A., Duncan E.L., Markie D.M., Robertson S.P.
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Publication state
Published
Issued date
04/08/2016
Peer-reviewed
Oui
Volume
99
Number
2
Pages
392-406
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor β (TGF-β)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C [p.Glu70Gln], c.299T>A [p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex.

Keywords
Adaptor Proteins, Signal Transducing/genetics, Adaptor Proteins, Signal Transducing/metabolism, Female, Filamins/genetics, Forehead/abnormalities, Humans, MAP Kinase Kinase Kinases/genetics, MAP Kinase Kinase Kinases/metabolism, MAP Kinase Signaling System/genetics, Male, Mutation/genetics, NF-kappa B/metabolism, Osteochondrodysplasias/genetics, Osteochondrodysplasias/metabolism, Phosphorylation, Protein Binding, Protein Multimerization, Signal Transduction/genetics
Pubmed
Open Access
Yes
Create date
24/07/2016 16:47
Last modification date
20/08/2019 16:47
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