Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome

EEC syndrome is an autosomal dominant disorder characterized by ectrodactyl y, ectodermal dysplasia, and facial clefts. We have mapped the genetic defe ct in several EEC syndrome families to a region of chromosome 3q27 previous ly implicated in the EEC-like disorder, limb mammary syndrome (LMS). Analys is of the p63 gene, a homolog of p53 located in the critical LMS/EEC interv al, revealed heterozygous mutations in nine unrelated EEC families. Eight m utations result in amino acid substitutions that are predicted to abolish t he DNA binding capacity of p63. The ninth is a frameshift mutation that aff ects the p63 alpha, but not p63 beta and p63 gamma isotypes. Transactivatio n studies with these mutant p63 isotypes provide a molecular explanation fo r the dominant character of p63 mutations in EEC syndrome.