p63 Gene Mutations in EEC Syndrome, Limb-Mammary Syndrome, and Isolated Split Hand–Split Foot Malformation Suggest a Genotype-Phenotype Correlation

Abstract

p63 mutations have been associated with EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate), as well as with nonsyndromic split hand-split foot malformation (SHFM). We performed p63 mutation analysis in a sample of 43 individuals and families affected with EEC syndrome, in 35 individuals affected with SHFM, and in three families with the EEC-like condition limb-mammary syndrome (LMS), which is characterized by ectrodactyly, cleft palate, and mammary-gland abnormalities. The results differed for these three conditions. p63 gene mutations were detected in almost all (40/43) individuals affected with EEC syndrome. Apart from a frameshift mutation in exon 13, all other EEC mutations were missense, predominantly involving codons 204, 227, 279, 280, and 304. In contrast, p63 mutations were detected in only a small proportion (4/35) of patients with isolated SHFM. p63 mutations in SHFM included three novel mutations: a missense mutation (K193E), a nonsense mutation (Q634X), and a mutation in the 3' splice site for exon 5. The fourth SHFM mutation (R280H) in this series was also found in a patient with classical EEC syndrome, suggesting partial overlap between the EEC and SHFM mutational spectra. The original family with LMS (van Bokhoven et al. 1999) had no detectable p63 mutation, although it clearly localizes to the p63 locus in 3q27. In two other small kindreds affected with LMS, frameshift mutations were detected in exons 13 and 14, respectively. The combined data show that p63 is the major gene for EEC syndrome, and that it makes a modest contribution to SHFM. There appears to be a genotype-phenotype correlation, in that there is a specific pattern of missense mutations in EEC syndrome that are not generally found in SHFM or LMS.

PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73

“…Although mutations in p63 and p73 do not occur frequently in human tumors, mutations in the p63 gene are the major cause of the EEC syndrome in humans (Celli et al, 1999;van Bokhoven et al, 2001). This autosomal dominant disorder is characterized by ectodactyly, ectodermal dysplasia and facial clefting.…”

TP63 gene mutation in ADULT syndrome

“…Whether this is a sporadic or familial case is not specified. 10 Finally, there is a considerable overlap between EEC, LMS, ADULT and lacrimo-auriculo-dento-digital syndromes ((LADD, MIM 149730, Table 1). Both linkage analysis in a three generations family described elsewhere, 11 and direct DNA sequencing in an isolated case excluded TP63 as the disease causing gene in LADD (personal data not shown).…”

Split hand/foot malformation due to chromosome 7q aberrations(SHFM1): additional support for functional haploinsufficiency as the causative mechanism

“…4 SHFM4 (3q27) results from mutations in the p63 gene. 5,6 The most common form, SHFM1, is caused by chromosomal rearrangements involving 7q21q22. 7,8 SHFM1 has been reported to be an autosomal dominant trait with reduced penetrance and variable expression.…”