EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences.

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• Germline mutations in TP63 are linked to human ectodermal dysplasia syndromes.
• The P63 protein plays a critical role in the development of ectoderm-derived tissues.

Purpose of the Study:

• To identify and functionally characterize novel TP63 alleles associated with ADULT and EEC syndromes.
• To investigate the impact of specific TP63 mutations on P63 protein function and DNA-binding domain activity.
• To correlate molecular findings with clinical variability in TP63-associated syndromes.

Main Methods:

• Identification and sequencing of TP63 alleles (G134V, insR155, G134D, R204W).
• Functional characterization in yeast and mammalian cell lines.
• Structural modeling based on the P63 DNA-binding domain crystal structure.

Main Results:

• The p.Arg243Trp mutant exhibited complete loss of transactivation and dominant-negative effects.
• Mutants p.Gly173Asp and p.Gly173Val showed impaired transactivation and interference with specific response elements (PERP, COL18A1).
• Structural modeling supported the distinct functional impacts of the characterized TP63 mutations.

Conclusions:

• The functional impact of TP63 mutations varies depending on the specific mutation and target response element.
• Understanding these distinct effects is crucial for explaining clinical variability in TP63-associated syndromes.
• Integrating diverse functional endpoints is essential for accurate assessment of TP63 mutation impacts.