RESUMO
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 ß (TGF-ß)-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.
Assuntos
Testa/anormalidades , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Mutação/genética , Osteocondrodisplasias/genética , Transdução de Sinais/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Feminino , Filaminas/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , NF-kappa B/metabolismo , Osteocondrodisplasias/metabolismo , Fosforilação , Ligação Proteica , Multimerização ProteicaRESUMO
Cleidocranial dysplasia (CCD) is a rare skeletal dysplasia characterised by a defect in ossification. Frequently reported clinical findings are delayed closure of the fontanelles and cranial sutures, hypoplastic clavicles, dental abnormalities and short stature. Our patient suffered from complete absence of ossification of both parietal bones. This is a rare and severe defect that has been reported in only a few patients with CCD.