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
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
Externí odkaz: