ArticleAmerican journal of human genetics2016
Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia.
Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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37 citing papers in PubMed, 70 citations in OpenAlex.
- TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development.PLoS biology · 2026Article
- Unraveling a Genetic Puzzle: CouldJournal of clinical research in pediatric endocrinology · 2026Article
- A NovelHuman mutation · 2026Article
- Further Exploring the TRRAP Genotype-Phenotype Correlations: Report of Three New Patients With A Focus on Skeletal Anomalies.Clinical genetics · 2026Article
- Genetic diagnosis and clinical characteristics analysis of cardiospondylocarpofacial syndrome in a Chinese family.Frontiers in pediatrics · 2025Article
- Combined Fronto-orbital Contouring and Orthognathic Surgery in Craniometaphyseal Dysplasia.Plastic and reconstructive surgery. Global open · 2024Article
- A severe case of cardiospondylocarpofacial syndrome with a novel MAP3K7 variant.Human genome variation · 2024Article
- Article
- Assigning pathogenicity for TAB2 variants using a novel scalable functional assay and expanding TAB2 disease spectrum.Human molecular genetics · 2023Article
- Integrated exome and transcriptome analysis prioritizes MAP4K4 de novo frameshift variants in autism spectrum disorder as a novel disease-gene association.Human genetics · 2023Article
- Sacral abnormalities including caudal appendage, skeletal dysplasia, and prenatal cardiomyopathy associated with a pathogenic TAB2 variant in a 3-generation family.American journal of medical genetics. Part A · 2022Article
- Expanding the phenotype of TAB2 variants and literature review.American journal of medical genetics. Part A · 2022Article
- The MAP3K7 gene: Further delineation of clinical characteristics and genotype/phenotype correlations.Human mutation · 2022Article
- Shortcutting the diagnostic odyssey: the multidisciplinary Program for Undiagnosed Rare Diseases in adults (UD-PrOZA).Orphanet journal of rare diseases · 2022Article
- TAB2 deficiency induces dilated cardiomyopathy by promoting RIPK1-dependent apoptosis and necroptosis.The Journal of clinical investigation · 2022Article
- TAB2 variants cause cardiovascular heart disease, connective tissue disorder, and developmental delay.Clinical genetics · 2022Article
- TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility.European journal of human genetics : EJHG · 2021Article
- A novel TAB2 mutation detected in a putative case of frontometaphyseal dysplasia.Human genome variation · 2021Article
- A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita.Genes · 2021Article
- Case Report: Pansynostosis, Chiari I Malformation and Syringomyelia in a Child With Frontometaphyseal Dysplasia 1.Frontiers in pediatrics · 2021Article
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Authors and funding
30 authors at 20 institutions in 10 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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