Mutations in MAP3K7 that alter the activity of the TAK1 signaling complex cause frontometaphyseal dysplasia

Wade, Emma M., Daniel, Philip B., Jenkins, Zandra A., McInerney-Leo, Aideen, Leo, Paul, Morgan, Tim, Addor, Marie Claude, Ades, Lesley C., Bertola, Debora, Bohring, Axel, Carter, Erin, Cho, Tae-Joon, Duba, Hans-Christoph, Fletcher, Elaine, Kim, Chong A., Krakow, Deborah, Morava, Eva, Neuhann, Teresa, Superti-Furga, Andrea, Veenstra-Knol, Irma, Wieczorek, Dagmar, Wilson, Louise C., Hennekam, Raoul C. M., Sutherland-Smith, Andrew J., Strom, Tim M., Wilkie, Andrew O. M., Brown, Matthew A., Duncan, Emma L., Markie, David M. and Robertson, Stephen P. (2016) Mutations in MAP3K7 that alter the activity of the TAK1 signaling complex cause frontometaphyseal dysplasia. American Journal of Human Genetics, 99 2: 392-406. doi:10.1016/j.ajhg.2016.05.024


Author Wade, Emma M.
Daniel, Philip B.
Jenkins, Zandra A.
McInerney-Leo, Aideen
Leo, Paul
Morgan, Tim
Addor, Marie Claude
Ades, Lesley C.
Bertola, Debora
Bohring, Axel
Carter, Erin
Cho, Tae-Joon
Duba, Hans-Christoph
Fletcher, Elaine
Kim, Chong A.
Krakow, Deborah
Morava, Eva
Neuhann, Teresa
Superti-Furga, Andrea
Veenstra-Knol, Irma
Wieczorek, Dagmar
Wilson, Louise C.
Hennekam, Raoul C. M.
Sutherland-Smith, Andrew J.
Strom, Tim M.
Wilkie, Andrew O. M.
Brown, Matthew A.
Duncan, Emma L.
Markie, David M.
Robertson, Stephen P.
Title Mutations in MAP3K7 that alter the activity of the TAK1 signaling complex cause frontometaphyseal dysplasia
Formatted title
Mutations in MAP3K7 that alter the activity of the TAK1 signaling complex cause frontometaphyseal dysplasia
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 1537-6605
0002-9297
Publication date 2016-08-04
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2016.05.024
Open Access Status Not yet assessed
Volume 99
Issue 2
Start page 392
End page 406
Total pages 15
Place of publication Cambridge, MA, United States
Publisher Cell Press
Collection year 2017
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 0 times in Thomson Reuters Web of Science Article
Scopus Citation Count Cited 2 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sat, 24 Sep 2016, 04:45:10 EST by System User on behalf of Learning and Research Services (UQ Library)