title: A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes.
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 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.
authors: Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
authors: Tuula
authors: T
authors: Rinne
authors: Suzanne E
authors: SE
authors: Clements
authors: Evert
authors: E
authors: Lamme
authors: Pascal H G
authors: PH
authors: Duijf
authors: Emine
authors: E
authors: Bolat
authors: Rowdy
authors: R
authors: Meijer
authors: Hans
authors: H
authors: Scheffer
authors: Elisabeth
authors: E
authors: Rosser
authors: Tiong Yang
authors: TY
authors: Tan
authors: John A
authors: JA
authors: McGrath
authors: Joost
authors: J
authors: Schalkwijk
authors: Han G
authors: HG
authors: Brunner
authors: Huiqing
authors: H
authors: Zhou
authors: Hans
authors: H
authors: van Bokhoven
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009056:Mouth Abnormalities / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis; D016415:Sequence Alignment; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C081876:CKAP4 protein, human; D018389:Codon, Nonsense; D008565:Membrane Proteins