| Abstract: |
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 p63α 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 ΔN-specific isoforms. Interestingly, this new ΔΔNp63 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 ΔNp63 protein with dominant effects. Given the nature of other RHS/AEC-like syndrome mutations, we conclude that these mutations affect only the ΔNp63α isoform and that this disruption is fundamental to explaining the clinical characteristics of these particular ectodermal dysplasia syndromes. © The Author 2008. Published by Oxford University Press. All rights reserved. |
| Keywords: |
human tissue; gene mutation; human cell; exon; codon, nonsense; case report; phenotype; animals; mice; cells, cultured; skin biopsy; membrane proteins; transcription, genetic; cell line, tumor; wild type; keratinocyte; amino acid sequence; molecular sequence data; amino terminal sequence; cell culture; blood sampling; sequence alignment; abnormalities, multiple; nucleotide sequence; protein biosynthesis; base sequence; protein p63; codon; keratinocytes; mutagenesis; isoprotein; methionine; genomic dna; polypeptide; translation regulation; trans-activation (genetics); aec syndrome; cleft lip palate; rapp hodgkin syndrome; ectodermal dysplasia; mouth abnormalities
|
| Notes: |
---
- "Cited By (since 1996): 16"
- "Export Date: 17 November 2011"
- "CODEN: HMGEE"
- "Molecular Sequence Numbers: GENBANK: AAG45610, AAK15622, AAN03691, AAP87985, AF075430, AF075431, BAB20631, CAC37099, NM_000526, NM_001002, NM_001101, NM_002046, NT_005612;"
- "Source: Scopus"
|
