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

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.

A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations

“…Previously published and present patients with TAB2 variants or chromosome deletions, defined by cytogenetic‐molecular tools and encompassing TAB2 , are reported in Table . Twenty‐two patients were identified with a highly variable phenotype, ranging from isolated CHD to systemic conditions with multiple malformations and intellectual disability/global developmental delay .…”

“…The 2 missense variants in patients with isolated CHD might cause partial loss‐of‐function . Conversely, the missense variant disclosed in the single FMD patient should lead to a gain‐of‐function mechanism …”

“…A 6q25.1 deletion encompassing TAB2 was also identified in a 3‐generation family with apparently isolated cardiac valve dysplasia and tetralogy of Fallot, as well as in a sporadic patient with multiple cardiac valve dysplasia, soft skin, joint hypermobility, unusual face, short limbs and stature . Finally, an apparently different phenotype, consistent with frontometaphyseal dysplasia (FMD), was identified in a patient with a TAB2 missense variant …”

30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology

“…It also activates JNK in responses to TGF-β signaling. Mutations in TAK1 have been clinically associated with Frontometaphyseal Dysplasia (FMD), a progressive skeletal dysplasia affecting the long bones and skull (Basart et al, 2015; Wade et al, 2016). …”

An N‐Ethyl‐N‐Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion

“…Conversely, osteoclast precursor‐specific Map3k7 knockout mice displayed skull overgrowth and increased trabecular bone, but again did not develop any vertebral abnormalities 62, 63. Furthermore, heterozygous mutations in MAP3K7 in humans cause the syndromic skeletal disorders of cardiospondylocarpofacial syndrome and frontometaphyseal dysplasia 64, 65. These studies illustrate that Map3k7 plays an important role in bone development, and it is possible that the HVF mice harbor a noncoding mutation within the critical interval that alters the regulation of Map3k7 specifically in developing vertebrae.…”