TP63 – Limb-Mammary Syndrome

Limb-mammary syndrome (LMS) is an autosomal dominant ectodermal dysplasia characterized by ectrodactyly, orofacial clefting, and mammary gland hypoplasia resulting from heterozygous TP63 variants. TP63 encodes a p53 family transcription factor essential for limb and mammary gland development with multiple isoforms that regulate epithelial stem cell renewal and differentiation.

Autosomal dominant inheritance of TP63-related LMS is supported by three multiplex families harboring heterozygous frameshift variants in the C-terminal sterile alpha motif: c.1411_1412del (p.Phe471fs) and c.1564del (p.Leu522fs), each segregating with disease (n=3 families) (PMID:11462173). An original LMS pedigree lacked detectable TP63 variants, indicating locus heterogeneity (PMID:11462173).

In addition, a sporadic case of LMS overlapping EEC and ADULT features was reported in a 13-year-old boy with a de novo missense variant c.674G>A (p.Arg225His) in TP63, correlating genotype with limb malformations, syndactyly, and tooth anomalies (PMID:33126320).

Functional assays demonstrate that LMS-associated TP63 variants act via a dominant-negative mechanism. Transactivation studies of C-terminal frameshift mutants show loss of DNA binding and repression of target promoters, while oligomerization defects disrupt p63 retention in the ER–Golgi compartment, consistent with ectodermal and mammary phenotypes (PMID:10535733). Differential gene expression profiling further distinguishes LMS from EEC, revealing unique transcriptomic signatures in peripheral blood of LMS patients (PMID:26075610).

Overall, there is moderate clinical validity for TP63 in LMS. Genetic evidence includes four unrelated probands (three familial, one sporadic) with distinct variant classes and segregation in three families. Functional evidence is concordant, demonstrating dominant-negative loss-of-function effects in vitro.

Key Take-home: Heterozygous TP63 variants cause autosomal dominant LMS via dominant-negative disruption of p63 transactivation, supporting molecular diagnosis and informing genetic counseling.

References

• Cell • 1999 • Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. PMID:10535733
• American journal of human genetics • 2001 • p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. PMID:11462173
• Medicine • 2020 • EEC-LM-ADULT syndrome caused by R319H mutation in TP63 with ectrodactyly, syndactyly, and teeth anomaly: A case report. PMID:33126320
• PloS one • 2015 • Differentially Expressed Genes in EEC and LMS Syndromes. PMID:26075610

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