File Download
There are no files associated with this item.
Links for fulltext
(May Require Subscription)
- Publisher Website: 10.1093/hmg/ddn094
- Scopus: eid_2-s2.0-45749128652
- PMID: 18364388
- WOS: WOS:000256978200009
- Find via
Supplementary
- Citations:
- Appears in Collections:
Article: A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes
Title | A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes |
---|---|
Authors | |
Issue Date | 2008 |
Publisher | Oxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/ |
Citation | Human Molecular Genetics, 2008, v. 17 n. 13, p. 1968-1977 How to Cite? |
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. |
Persistent Identifier | http://hdl.handle.net/10722/170401 |
ISSN | 2023 Impact Factor: 3.1 2023 SCImago Journal Rankings: 1.602 |
ISI Accession Number ID | |
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Rinne, T | en_US |
dc.contributor.author | Clements, SE | en_US |
dc.contributor.author | Lamme, E | en_US |
dc.contributor.author | Duijf, PHG | en_US |
dc.contributor.author | Bolat, E | en_US |
dc.contributor.author | Meijer, R | en_US |
dc.contributor.author | Scheffer, H | en_US |
dc.contributor.author | Rosser, E | en_US |
dc.contributor.author | Tan, TY | en_US |
dc.contributor.author | Mcgrath, JA | en_US |
dc.contributor.author | Schalkwijk, J | en_US |
dc.contributor.author | Brunner, HG | en_US |
dc.contributor.author | Zhou, H | en_US |
dc.contributor.author | Van Bokhoven, H | en_US |
dc.date.accessioned | 2012-10-30T06:08:03Z | - |
dc.date.available | 2012-10-30T06:08:03Z | - |
dc.date.issued | 2008 | en_US |
dc.identifier.citation | Human Molecular Genetics, 2008, v. 17 n. 13, p. 1968-1977 | en_US |
dc.identifier.issn | 0964-6906 | en_US |
dc.identifier.uri | http://hdl.handle.net/10722/170401 | - |
dc.description.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. | en_US |
dc.language | eng | en_US |
dc.publisher | Oxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/ | en_US |
dc.relation.ispartof | Human Molecular Genetics | en_US |
dc.subject.mesh | Abnormalities, Multiple - Genetics - Metabolism | en_US |
dc.subject.mesh | Adolescent | en_US |
dc.subject.mesh | Amino Acid Sequence | en_US |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Base Sequence | en_US |
dc.subject.mesh | Cell Line, Tumor | en_US |
dc.subject.mesh | Cells, Cultured | en_US |
dc.subject.mesh | Child | en_US |
dc.subject.mesh | Child, Preschool | en_US |
dc.subject.mesh | Codon, Nonsense | en_US |
dc.subject.mesh | Ectodermal Dysplasia - Genetics - Metabolism | en_US |
dc.subject.mesh | Female | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Keratinocytes - Metabolism | en_US |
dc.subject.mesh | Male | en_US |
dc.subject.mesh | Membrane Proteins - Chemistry - Genetics - Metabolism | en_US |
dc.subject.mesh | Mice | en_US |
dc.subject.mesh | Molecular Sequence Data | en_US |
dc.subject.mesh | Mouth Abnormalities - Embryology - Genetics - Metabolism | en_US |
dc.subject.mesh | Protein Biosynthesis | en_US |
dc.subject.mesh | Sequence Alignment | en_US |
dc.subject.mesh | Transcription, Genetic | en_US |
dc.subject.mesh | Transcriptional Activation | en_US |
dc.title | A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes | en_US |
dc.type | Article | en_US |
dc.identifier.email | Tan, TY:tanty@hku.hk | en_US |
dc.identifier.authority | Tan, TY=rp01380 | en_US |
dc.description.nature | link_to_subscribed_fulltext | en_US |
dc.identifier.doi | 10.1093/hmg/ddn094 | en_US |
dc.identifier.pmid | 18364388 | en_US |
dc.identifier.scopus | eid_2-s2.0-45749128652 | en_US |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-45749128652&selection=ref&src=s&origin=recordpage | en_US |
dc.identifier.volume | 17 | en_US |
dc.identifier.issue | 13 | en_US |
dc.identifier.spage | 1968 | en_US |
dc.identifier.epage | 1977 | en_US |
dc.identifier.isi | WOS:000256978200009 | - |
dc.publisher.place | United Kingdom | en_US |
dc.identifier.scopusauthorid | Rinne, T=8371327600 | en_US |
dc.identifier.scopusauthorid | Clements, SE=27168952100 | en_US |
dc.identifier.scopusauthorid | Lamme, E=6701330052 | en_US |
dc.identifier.scopusauthorid | Duijf, PHG=6506948308 | en_US |
dc.identifier.scopusauthorid | Bolat, E=6602080518 | en_US |
dc.identifier.scopusauthorid | Meijer, R=24169324600 | en_US |
dc.identifier.scopusauthorid | Scheffer, H=7006534904 | en_US |
dc.identifier.scopusauthorid | Rosser, E=7004000259 | en_US |
dc.identifier.scopusauthorid | Tan, TY=8567188100 | en_US |
dc.identifier.scopusauthorid | Mcgrath, JA=7402677631 | en_US |
dc.identifier.scopusauthorid | Schalkwijk, J=7006301869 | en_US |
dc.identifier.scopusauthorid | Brunner, HG=7402010860 | en_US |
dc.identifier.scopusauthorid | Zhou, H=12792008500 | en_US |
dc.identifier.scopusauthorid | Van Bokhoven, H=7005587499 | en_US |
dc.identifier.issnl | 0964-6906 | - |