A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes

Hum Mol Genet. 2008 Jul 1;17(13):1968-77. doi: 10.1093/hmg/ddn094. Epub 2008 Mar 25.


Missense mutations in the 3' end of the p63 gene are associated with either RHS (Rapp-Hodgkin syndrome) or AEC (Ankyloblepharon Ectodermal defects Cleft lip/palate) syndrome. These mutations give rise to mutant p63alpha protein isoforms with dominant effects towards their wild-type counterparts. Here we report four RHS/AEC-like patients with mutations (p.Gln9fsX23, p.Gln11X, p.Gln16X), that introduce premature termination codons in the N-terminal part of the p63 protein. These mutations appear to be incompatible with the current paradigms of dominant-negative/gain-of-function outcomes for other p63 mutations. Moreover it is difficult to envisage how the remaining small N-terminal polypeptide contributes to a dominant disease mechanism. Primary keratinocytes from a patient containing the p.Gln11X mutation revealed a normal and aberrant p63-related protein that was just slightly smaller than the wild-type p63. We show that the smaller p63 protein is produced by translation re-initiation at the next downstream methionine, causing truncation of a non-canonical transactivation domain in the DeltaN-specific isoforms. Interestingly, this new DeltaDeltaNp63 isoform is also present in the wild-type keratinocytes albeit in small amounts compared with the p.Gln11X patient. These data establish that the p.Gln11X-mutation does not represent a null-allele leading to haploinsufficiency, but instead gives rise to a truncated DeltaNp63 protein with dominant effects. Given the nature of other RHS/AEC-like syndrome mutations, we conclude that these mutations affect only the DeltaNp63alpha isoform and that this disruption is fundamental to explaining the clinical characteristics of these particular ectodermal dysplasia syndromes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / metabolism
  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Codon, Nonsense*
  • Ectodermal Dysplasia / genetics*
  • Ectodermal Dysplasia / metabolism
  • Female
  • Humans
  • Keratinocytes / metabolism
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Mouth Abnormalities / embryology
  • Mouth Abnormalities / genetics*
  • Mouth Abnormalities / metabolism
  • Protein Biosynthesis*
  • Sequence Alignment
  • Transcription, Genetic
  • Transcriptional Activation


  • CKAP4 protein, human
  • Codon, Nonsense
  • Membrane Proteins

Associated data

  • GENBANK/AAG45610
  • GENBANK/AAK15622
  • GENBANK/AAN03691
  • GENBANK/AAP87985
  • GENBANK/BAB20631
  • GENBANK/CAC37099
  • RefSeq/NM_000526
  • RefSeq/NM_001002
  • RefSeq/NM_001101
  • RefSeq/NM_002046