Genetic and functional studies of a germline TP53 splicing mutation in a Li-Fraumeni-like family.

2.50
Hdl Handle:
http://hdl.handle.net/10541/92734
Title:
Genetic and functional studies of a germline TP53 splicing mutation in a Li-Fraumeni-like family.
Authors:
Varley, Jennifer; Chapman, P; McGown, Gail; Thorncroft, Mary R; White, Gavin R M; Greaves, M J; Scott, David; Spreadborough, Anne R; Tricker, K J; Birch, Jillian M; Evans, D Gareth R; Reddel, R; Camplejohn, R S; Burn, J; Boyle, John M
Abstract:
We report an extensive Li-Fraumeni-like family in which there is an unusual spectrum of tumours at relatively late onset. A germline TP53 splice donor mutation in exon 4 is present in all affected family members available for testing. The mutation abolishes correct splicing of intron 4 and techniques of RT-PCR have identified three different aberrant transcripts from the mutant TP53 allele. Using the yeast functional assay to analyse transcripts in cells from a number of family members with the mutant allele, TP53 appears wild-type. Functional studies have been carried out on cells from patients with and without cancer who carry the germline mutation, and on cells from unaffected individuals from the same family who do not carry the mutation. Using a number of functional endpoints known to distinguish between cells carrying mutant or wild-type TP53 alleles, we were unable to discriminate normal (wt/wt) from heterozygous (wt/mut) cells by lymphocyte apoptosis and fibroblast survival following low dose rate ionising radiation exposure. However germline mutation carriers show increased sensitivity to radiation-induced chromosome damage in the G2 phase of the cell cycle, and decreased transient and permanent G1 arrest. These studies demonstrate the importance of fully characterising the effects of TP53 germline mutations, and may explain some of the phenotypic features of this family.
Affiliation:
CRC Section of Molecular Genetics, Paterson Institute for Cancer Research, Manchester, UK.
Citation:
Genetic and functional studies of a germline TP53 splicing mutation in a Li-Fraumeni-like family. 1998, 16 (25):3291-8 Oncogene
Journal:
Oncogene
Issue Date:
25-Jun-1998
URI:
http://hdl.handle.net/10541/92734
DOI:
10.1038/sj.onc.1201878
PubMed ID:
9681828
Type:
Article
Language:
en
ISSN:
0950-9232
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorVarley, Jenniferen
dc.contributor.authorChapman, Pen
dc.contributor.authorMcGown, Gailen
dc.contributor.authorThorncroft, Mary Ren
dc.contributor.authorWhite, Gavin R Men
dc.contributor.authorGreaves, M Jen
dc.contributor.authorScott, Daviden
dc.contributor.authorSpreadborough, Anne Ren
dc.contributor.authorTricker, K Jen
dc.contributor.authorBirch, Jillian Men
dc.contributor.authorEvans, D Gareth Ren
dc.contributor.authorReddel, Ren
dc.contributor.authorCamplejohn, R Sen
dc.contributor.authorBurn, Jen
dc.contributor.authorBoyle, John Men
dc.date.accessioned2010-02-23T11:06:41Z-
dc.date.available2010-02-23T11:06:41Z-
dc.date.issued1998-06-25-
dc.identifier.citationGenetic and functional studies of a germline TP53 splicing mutation in a Li-Fraumeni-like family. 1998, 16 (25):3291-8 Oncogeneen
dc.identifier.issn0950-9232-
dc.identifier.pmid9681828-
dc.identifier.doi10.1038/sj.onc.1201878-
dc.identifier.urihttp://hdl.handle.net/10541/92734-
dc.description.abstractWe report an extensive Li-Fraumeni-like family in which there is an unusual spectrum of tumours at relatively late onset. A germline TP53 splice donor mutation in exon 4 is present in all affected family members available for testing. The mutation abolishes correct splicing of intron 4 and techniques of RT-PCR have identified three different aberrant transcripts from the mutant TP53 allele. Using the yeast functional assay to analyse transcripts in cells from a number of family members with the mutant allele, TP53 appears wild-type. Functional studies have been carried out on cells from patients with and without cancer who carry the germline mutation, and on cells from unaffected individuals from the same family who do not carry the mutation. Using a number of functional endpoints known to distinguish between cells carrying mutant or wild-type TP53 alleles, we were unable to discriminate normal (wt/wt) from heterozygous (wt/mut) cells by lymphocyte apoptosis and fibroblast survival following low dose rate ionising radiation exposure. However germline mutation carriers show increased sensitivity to radiation-induced chromosome damage in the G2 phase of the cell cycle, and decreased transient and permanent G1 arrest. These studies demonstrate the importance of fully characterising the effects of TP53 germline mutations, and may explain some of the phenotypic features of this family.en
dc.language.isoenen
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAdult-
dc.subject.meshAlternative Splicing-
dc.subject.meshApoptosis-
dc.subject.meshFamily Health-
dc.subject.meshFemale-
dc.subject.meshFibroblasts-
dc.subject.meshGerm-Line Mutation-
dc.subject.meshHumans-
dc.subject.meshLi-Fraumeni Syndrome-
dc.subject.meshLymphocytes-
dc.subject.meshMale-
dc.subject.meshPedigree-
dc.subject.meshPoint Mutation-
dc.subject.meshTumor Suppressor Protein p53-
dc.subject.meshYeasts-
dc.titleGenetic and functional studies of a germline TP53 splicing mutation in a Li-Fraumeni-like family.en
dc.typeArticleen
dc.contributor.departmentCRC Section of Molecular Genetics, Paterson Institute for Cancer Research, Manchester, UK.en
dc.identifier.journalOncogeneen

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