MAP3K7 – Frontometaphyseal Dysplasia Type 2

Frontometaphyseal dysplasia type 2 (FMD2) is an X-linked recessive–like skeletal dysplasia manifesting with supraorbital hyperostosis, undermodeling of long bones, joint contractures and extraskeletal features such as skin anomalies and neural tube defects. Caused by heterozygous gain-of-function mutations in MAP3K7, FMD2 displays hallmark craniofacial and long bone abnormalities with variable expressivity. MAP3K7 encodes the transforming growth factor-β–activated kinase 1 (TAK1), a serine/threonine kinase that mediates TGF-β and cytokine-induced signaling critical for osteogenesis (PMID:29660408).

To date, fewer than 20 patients with FMD2 have been reported, almost all harboring the recurrent c.1454C>T (p.Pro485Leu) missense variant in MAP3K7. In the seminal study, a 17-year-old male presented de novo with classical skeletal features—prominent supraorbital ridges, undermodeled diaphyses, flexion contractures—and extraskeletal findings including keloid scars, growth retardation and spina bifida occulta, expanding the clinical spectrum of FMD2 (PMID:29660408).

Inheritance is autosomal dominant with de novo occurrences in nearly all cases; no multigenerational segregation has been observed to date. Segregation analysis confirms the absence of the variant in parental samples, supporting high penetrance and a gain-of-function mechanism for p.Pro485Leu. No additional affected relatives have been reported.

The variant spectrum in FMD2 is narrow: all pathogenic alleles reported to date are missense substitutions clustered in the kinase activation loop of TAK1. The recurrent c.1454C>T (p.Pro485Leu) alteration disrupts local conformation and is associated with a more severe skeletal phenotype compared to other domain variants.

Although direct functional assays of the p.Pro485Leu variant in patient-derived cells are limited, MAP3K7’s role in TGF-β–mediated osteogenic signaling provides mechanistic plausibility. Gain-of-function TAK1 activity likely enhances downstream SMAD and MAPK pathways, leading to aberrant osteoblast differentiation and hyperostosis.

Integration of genetic and limited experimental data supports a Moderate clinical validity for MAP3K7–FMD2 association. The recurrent de novo p.Pro485Leu missense variant in multiple unrelated probands, combined with MAP3K7’s established role in bone formation, underpins diagnostic testing and risk assessment. Key take-home: heterozygous c.1454C>T (p.Pro485Leu) in MAP3K7 is a reliable molecular marker for FMD2, guiding clinical management.

References

• European journal of medical genetics • 2018 • Expansion of the clinical spectrum of frontometaphyseal dysplasia 2 caused by the recurrent mutation p.Pro485Leu in MAP3K7. PMID:29660408

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