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Frontometaphyseal dysplasia (FMD) is a progressive autosomal dominant skeletal dysplasia characterized by hyperostosis of long bones and cranial vault, facial dysmorphism, and a predisposition to keloid formation. In a cohort of 19 FLNA‐negative probands, whole‐exome sequencing identified four heterozygous MAP3K7 mutations, including a recurrent de novo c.1454C>T (p.Pro485Leu) variant in 15 unrelated individuals and three additional missense changes in the kinase domain (PMID:27426733). A subsequent clinical evaluation of 20 AD‐FMD patients confirmed 15 cases with the same c.1454C>T (p.Pro485Leu) and three with N‐terminal kinase domain variants, further supporting autosomal dominant inheritance and mutational recurrence (PMID:28498505). No familial segregation beyond de novo events was observed, consistent with a gain‐of‐function mechanism.
The mutational spectrum comprises one highly recurrent hotspot and three additional missense alleles (c.208G>C (p.Glu70Gln); c.299T>A (p.Val100Glu); c.502G>C (p.Gly168Arg)), all absent from population databases and predicted deleterious by multiple in silico tools (PMID:27426733). These variants affect conserved residues in the kinase domain or its proximal regulatory regions, correlating with phenotypic variability: kinase‐domain mutations yield a milder skeletal phenotype compared to the Pro485Leu hotspot.
Functional assays of the p.Pro485Leu variant revealed increased TAK1 autophosphorylation without destabilizing the protein or impairing TAB2 binding, leading to dysregulation of downstream NF-κB and MAPK signaling pathways in cellular models (PMID:27426733). This gain‐of‐function effect phenocopies FLNA‐related FMD, implicating hyperactive TAK1 signaling in pathogenesis. Rescue experiments were not reported, but the consistency of signaling perturbation across assays provides moderate functional support.
Clinically, individuals present with long bone thickening, cranial hyperostosis, hearing impairment (HP:0000365), valgus deformity of the feet (HP:0008081), occasional intellectual disability (HP:0001249), and cleft palate (HP:0000175), mirroring features of FLNA‐positive FMD but with increased keloid susceptibility (PMID:28498505). No conflicting reports have been published that refute this association or assign alternative phenotypes to MAP3K7 variants in FMD.
Collectively, the identification of 18 de novo MAP3K7 variants across two independent cohorts, coupled with concordant gain‐of‐function assays, supports a Strong gene‐disease association under ClinGen criteria. MAP3K7 testing should be incorporated into diagnostic panels for FMD to facilitate early genetic diagnosis and inform clinical management. Key take‐home: Gain‐of‐function MAP3K7 variants cause autosomal dominant frontometaphyseal dysplasia through hyperactive TAK1 signaling, supporting both diagnostic and therapeutic strategies.
Gene–Disease AssociationStrong18 de novo MAP3K7 variants in unrelated probands, including 15 recurrent c.1454C>T (p.Pro485Leu), with consistent phenotypic recurrence and functional concordance Genetic EvidenceStrongFour distinct missense mutations identified in two independent cohorts of 19 and 20 probands with autosomal dominant FMD, including a recurrent hotspot in 15 cases ([PMID:27426733]; [PMID:28498505]) Functional EvidenceModeratep.Pro485Leu variant increases TAK1 autophosphorylation and dysregulates NF-κB and MAPK signaling, consistent with a gain-of-function mechanism ([PMID:27426733]) |