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

TitleA novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes
Authors
Issue Date2008
PublisherOxford 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?
AbstractMissense 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 Identifierhttp://hdl.handle.net/10722/170401
ISSN
2015 Impact Factor: 5.985
2015 SCImago Journal Rankings: 4.288
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorRinne, Ten_US
dc.contributor.authorClements, SEen_US
dc.contributor.authorLamme, Een_US
dc.contributor.authorDuijf, PHGen_US
dc.contributor.authorBolat, Een_US
dc.contributor.authorMeijer, Ren_US
dc.contributor.authorScheffer, Hen_US
dc.contributor.authorRosser, Een_US
dc.contributor.authorTan, TYen_US
dc.contributor.authorMcgrath, JAen_US
dc.contributor.authorSchalkwijk, Jen_US
dc.contributor.authorBrunner, HGen_US
dc.contributor.authorZhou, Hen_US
dc.contributor.authorVan Bokhoven, Hen_US
dc.date.accessioned2012-10-30T06:08:03Z-
dc.date.available2012-10-30T06:08:03Z-
dc.date.issued2008en_US
dc.identifier.citationHuman Molecular Genetics, 2008, v. 17 n. 13, p. 1968-1977en_US
dc.identifier.issn0964-6906en_US
dc.identifier.urihttp://hdl.handle.net/10722/170401-
dc.description.abstractMissense 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.languageengen_US
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/en_US
dc.relation.ispartofHuman Molecular Geneticsen_US
dc.subject.meshAbnormalities, Multiple - Genetics - Metabolismen_US
dc.subject.meshAdolescenten_US
dc.subject.meshAmino Acid Sequenceen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBase Sequenceen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCells, Cultureden_US
dc.subject.meshChilden_US
dc.subject.meshChild, Preschoolen_US
dc.subject.meshCodon, Nonsenseen_US
dc.subject.meshEctodermal Dysplasia - Genetics - Metabolismen_US
dc.subject.meshFemaleen_US
dc.subject.meshHumansen_US
dc.subject.meshKeratinocytes - Metabolismen_US
dc.subject.meshMaleen_US
dc.subject.meshMembrane Proteins - Chemistry - Genetics - Metabolismen_US
dc.subject.meshMiceen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshMouth Abnormalities - Embryology - Genetics - Metabolismen_US
dc.subject.meshProtein Biosynthesisen_US
dc.subject.meshSequence Alignmenten_US
dc.subject.meshTranscription, Geneticen_US
dc.subject.meshTranscriptional Activationen_US
dc.titleA novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromesen_US
dc.typeArticleen_US
dc.identifier.emailTan, TY:tanty@hku.hken_US
dc.identifier.authorityTan, TY=rp01380en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1093/hmg/ddn094en_US
dc.identifier.pmid18364388en_US
dc.identifier.scopuseid_2-s2.0-45749128652en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-45749128652&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume17en_US
dc.identifier.issue13en_US
dc.identifier.spage1968en_US
dc.identifier.epage1977en_US
dc.identifier.isiWOS:000256978200009-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridRinne, T=8371327600en_US
dc.identifier.scopusauthoridClements, SE=27168952100en_US
dc.identifier.scopusauthoridLamme, E=6701330052en_US
dc.identifier.scopusauthoridDuijf, PHG=6506948308en_US
dc.identifier.scopusauthoridBolat, E=6602080518en_US
dc.identifier.scopusauthoridMeijer, R=24169324600en_US
dc.identifier.scopusauthoridScheffer, H=7006534904en_US
dc.identifier.scopusauthoridRosser, E=7004000259en_US
dc.identifier.scopusauthoridTan, TY=8567188100en_US
dc.identifier.scopusauthoridMcgrath, JA=7402677631en_US
dc.identifier.scopusauthoridSchalkwijk, J=7006301869en_US
dc.identifier.scopusauthoridBrunner, HG=7402010860en_US
dc.identifier.scopusauthoridZhou, H=12792008500en_US
dc.identifier.scopusauthoridVan Bokhoven, H=7005587499en_US

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