TP63 and split hand-foot malformation 4

The TP63 gene encoding the p53 homolog is implicated in several developmental syndromes characterized by limb malformations, including split hand-foot malformation 4. Heterozygous missense mutations at Arg298 (c.728G>A (p.Arg243Gln)) have been reported in five unrelated families with ADULT syndrome, which includes ectrodactyly reminiscent of SHFM4 (PMID:16724007). Although these families are clinically diagnosed with ADULT syndrome rather than SHFM4, the phenotypic overlap provides indirect genetic evidence for TP63 involvement in SHFM4. Functional studies demonstrate that the p.Arg243Gln variant confers a gain-of-function effect on the ΔNp63γ isoform, revealing a second activation domain in p63 and mechanistically linking the mutation to altered limb development (PMID:11929852). No segregation data specific to SHFM4 are available, and no direct SHFM4 cases have been reported. Thus, the clinical validity is currently limited, pending identification of SHFM4-specific probands. Key take-home: TP63 missense mutations at Arg298 may underlie split hand-foot malformation 4 through ΔNp63γ gain-of-function.

References

• European Journal of Human Genetics • 2006 • Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene. PMID:16724007
• Human Molecular Genetics • 2002 • Gain-of-function mutation in ADULT syndrome reveals the presence of a second transactivation domain in p63. PMID:11929852

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