title: Investigations on a clinically and functionally unusual and novel germline p53 mutation.
abstract: This report describes an individual with a rare choroid plexus papilloma in adulthood (age 29) after earlier having an osteosarcoma (age 22). The results from this study, and others, suggest that it may be advisable to consider the possibility of a germline p53 mutation in adults presenting with choroid plexus tumours. In the current study automated DNA sequencing of genomic DNA detected a novel germline 7 base pair insertion in exon 5 of the p53 gene in this patient. The alteration in frame would produce amino acid substitutions beginning with alanine to glycine at position 161 and a stop codon at position 182 in the mutated protein. Surprisingly two assays of p53 function gave apparently wild-type results on peripheral blood lymphocytes from this individual. These results led us to carry out more detailed functional tests on the mutant protein. The mutant allele was expressed either at very low levels or not at all in phytohaemagglutinin stimulated lymphocytes. Further, the mutant protein was completely non-functional in terms of its ability to transactivate a series of p53-responsive genes (p21(WAF1), bax, PIG3), to transrepress a target gene and to inhibit colony growth in transfected Saos-2 cells. However, surprisingly, data from irradiated peripheral blood lymphocytes and transfected Saos-2 cells, suggested that this truncated, mutant protein retains significant ability to induce apoptosis.
authors.affiliation: Richard Dimbleby Department Cancer Research, Guy's, King's and St Thomas' School of Medicine, St Thomas' Hospital, London SE1 7EH, UK.
authors.forename: J
authors.initials: J
authors.lastname: Rutherford
authors.forename: C E
authors.initials: CE
authors.lastname: Chu
authors.forename: P M
authors.initials: PM
authors.lastname: Duddy
authors.forename: R S
authors.initials: RS
authors.lastname: Charlton
authors.forename: P
authors.initials: P
authors.lastname: Chumas
authors.forename: G R
authors.initials: GR
authors.lastname: Taylor
authors.forename: X
authors.initials: X
authors.lastname: Lu
authors.forename: D M
authors.initials: DM
authors.lastname: Barnes
authors.forename: R S
authors.initials: RS
authors.lastname: Camplejohn
mesh_terms: D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D017209:Apoptosis; D001483:Base Sequence; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D016545:Choroid Plexus Neoplasms / Q000235:genetics*; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008214:Lymphocytes / Q000473:pathology / Q000528:radiation effects; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D016609:Neoplasms, Second Primary / Q000235:genetics*; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D010212:Papilloma / Q000235:genetics*; D010375:Pedigree; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000473:pathology; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*
chemical_list: D018389:Codon, Nonsense; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53