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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
13
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pubmed:dateCreated |
2008-6-16
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pubmed:databankReference |
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1460-2083
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pubmed:author |
pubmed-author:BolatEmineE,
pubmed-author:BrunnerHan GHG,
pubmed-author:ClementsSuzanne ESE,
pubmed-author:DuijfPascal H GPH,
pubmed-author:LammeEvertE,
pubmed-author:McGrathJohn AJA,
pubmed-author:MeijerRowdyR,
pubmed-author:RinneTuulaT,
pubmed-author:RosserElisabethE,
pubmed-author:SchalkwijkJoostJ,
pubmed-author:SchefferHansH,
pubmed-author:TanTiong YangTY,
pubmed-author:ZhouHuiqingH,
pubmed-author:van BokhovenHansH
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
17
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1968-77
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:18364388-Abnormalities, Multiple,
pubmed-meshheading:18364388-Adolescent,
pubmed-meshheading:18364388-Amino Acid Sequence,
pubmed-meshheading:18364388-Animals,
pubmed-meshheading:18364388-Base Sequence,
pubmed-meshheading:18364388-Cell Line, Tumor,
pubmed-meshheading:18364388-Cells, Cultured,
pubmed-meshheading:18364388-Child,
pubmed-meshheading:18364388-Child, Preschool,
pubmed-meshheading:18364388-Codon, Nonsense,
pubmed-meshheading:18364388-Ectodermal Dysplasia,
pubmed-meshheading:18364388-Female,
pubmed-meshheading:18364388-Humans,
pubmed-meshheading:18364388-Keratinocytes,
pubmed-meshheading:18364388-Male,
pubmed-meshheading:18364388-Membrane Proteins,
pubmed-meshheading:18364388-Mice,
pubmed-meshheading:18364388-Molecular Sequence Data,
pubmed-meshheading:18364388-Mouth Abnormalities,
pubmed-meshheading:18364388-Protein Biosynthesis,
pubmed-meshheading:18364388-Sequence Alignment,
pubmed-meshheading:18364388-Transcription, Genetic,
pubmed-meshheading:18364388-Transcriptional Activation
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pubmed:year |
2008
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pubmed:articleTitle |
A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes.
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pubmed:affiliation |
Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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