A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes
| Autor: | Elisabeth Rosser, Suzanne E. Clements, Rowdy Meijer, Evert N. Lamme, Pascal H.G. Duijf, Han G. Brunner, John A. McGrath, Emine Bolat, Huiqing Zhou, Hans van Bokhoven, Tiong Yang Tan, Joost Schalkwijk, Hans Scheffer, Tuula Rinne |
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| Rok vydání: | 2008 |
| Předmět: |
Keratinocytes
Male Transcriptional Activation Gene isoform Ectodermal dysplasia Hay–Wells syndrome Genetics and epigenetic pathways of disease [NCMLS 6] Adolescent Transcription Genetic Molecular Sequence Data Mutant Biology medicine.disease_cause Genomic disorders and inherited multi-system disorders [IGMD 3] Mice Translational research [ONCOL 3] Ectodermal Dysplasia Cell Line Tumor Genetics medicine Animals Humans Missense mutation Abnormalities Multiple Amino Acid Sequence Child Molecular Biology Gene Cells Cultured Genetics (clinical) Chronic inflammation and autoimmunity [UMCN 4.2] Mutation Base Sequence Membrane Proteins General Medicine medicine.disease Pathogenesis and modulation of inflammation [N4i 1] Genetic defects of metabolism [UMCN 5.1] Codon Nonsense Child Preschool Protein Biosynthesis Female Mouth Abnormalities Haploinsufficiency Functional Neurogenomics [DCN 2] Infection and autoimmunity [NCMLS 1] Sequence Alignment Immunity infection and tissue repair [NCMLS 1] |
| Zdroj: | Human Molecular Genetics, 17, 1968-1977 Human Molecular Genetics, 17, 13, pp. 1968-1977 |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Contains fulltext : 69170.pdf (Publisher’s version ) (Open Access) 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. 9 p. |
| Databáze: | OpenAIRE |
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