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Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia
Emma M Wade1, Philip B Daniel1, Zandra A Jenkins1
1Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
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.
Insights
Mutations in MAP3K7 and TAB2 cause frontometaphyseal dysplasia (FMD), mimicking FLNA mutations. These genetic changes disrupt the TAK1 complex, revealing new insights into FMD pathogenesis and related skeletal disorders.
Area of Science:
- Genetics
- Skeletal Dysplasias
- Molecular Biology
Background:
- Frontometaphyseal dysplasia (FMD) is a progressive skeletal disorder characterized by bone overgrowth.
- While FLNA mutations explain some FMD cases, many patients lack identified mutations but share similar phenotypes, often with keloid scarring.
- The underlying genetic causes for a significant portion of FMD cases remain elusive.
Purpose of the Study:
- To identify the genetic basis of FMD in individuals without FLNA mutations.
- To investigate the functional consequences of identified mutations on protein function and signaling pathways.
- To elucidate the molecular mechanisms linking genetic defects to FMD and related filaminopathies.
Main Methods:
- Whole-exome sequencing and Sanger sequencing were employed in 19 FMD patients lacking FLNA mutations.
- Genetic variants in MAP3K7 (encoding TAK1) and TAB2 were identified and analyzed.
- Functional studies assessed the impact of mutations on TAK1 protein stability, dimerization, binding, and signaling activity.
Main Results:
- Mutations in MAP3K7 and TAB2 were identified as causes of FMD in FLNA-negative individuals.
- A recurrent MAP3K7 mutation (p.Pro485Leu) and missense mutations (p.Glu70Gln, p.Val100Glu, p.Gly168Arg) were found, with the latter associated with milder phenotypes.
- A de novo TAB2 mutation (p.Glu569Lys) was also identified.
- The recurrent MAP3K7 mutation increased TAK1 autophosphorylation and altered signaling pathway activity without affecting protein stability or binding.
Conclusions:
- Dysregulation of the TAK1 complex, through MAP3K7 or TAB2 mutations, closely mimics FMD caused by FLNA mutations.
- These findings suggest that signaling pathways regulated by the TAK1 complex are critical in FMD pathogenesis.
- The study proposes that misregulation of TAK1 signaling may contribute to the pathophysiology of some FLNA-related filaminopathies.
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