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dc.contributor.authorKeith, WNen_US
dc.contributor.authorVulliamy, Ten_US
dc.contributor.authorZhao, Jen_US
dc.contributor.authorAr, Cen_US
dc.contributor.authorErzik, Cen_US
dc.contributor.authorBilsland, Aen_US
dc.contributor.authorUlku, Ben_US
dc.contributor.authorMarrone, Aen_US
dc.contributor.authorMason, PJen_US
dc.contributor.authorBessler, Men_US
dc.contributor.authorSerakinci, Nen_US
dc.contributor.authorDokal, Ien_US
dc.date.accessioned2016-08-22T13:30:54Z
dc.date.available2004-06-22en_US
dc.date.issued2004-06-22en_US
dc.date.submitted2016-08-02T13:19:32.587Z
dc.identifier.issn1471-2326en_US
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/14846
dc.description.abstractBACKGROUND: Mutations in the gene coding for the RNA component of telomerase, hTERC, have been found in autosomal dominant dyskeratosis congenita (DC) and aplastic anemia. Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal blood disorder associated with aplastic anemia and characterized by the presence of one or more clones of blood cells lacking glycosylphosphatidylinositol (GPI) anchored proteins due to a somatic mutation in the PIGA gene. METHODS: We searched for mutations in DNA extracted from PNH patients by amplification of the hTERC gene and denaturing high performance liquid chromatography (dHPLC). After a mutation was found in a potential transcription factor binding site in one patient electrophoretic mobility shift assays were used to detect binding of transcription factors to that site. The effect of the mutation on the function of the promoter was tested by transient transfection constructs in which the promoter is used to drive a reporter gene. RESULTS: Here we report the finding of a novel promoter mutation (-99C->G) in the hTERC gene in a patient with PNH. The mutation disrupts an Sp1 binding site and destroys its ability to bind Sp1. Transient transfection assays show that mutations in this hTERC site including C-99G cause either up- or down-regulation of promoter activity and suggest that the site regulates core promoter activity in a context dependent manner in cancer cells. CONCLUSIONS: These data are the first report of an hTERC promoter mutation from a patient sample which can modulate core promoter activity in vitro, raising the possibility that the mutation may affect the transcription of the gene in hematopoietic stem cells in vivo, and that dysregulation of telomerase may play a role in the development of bone marrow failure and the evolution of PNH clones.en_US
dc.format.extent3 - ?en_US
dc.languageengen_US
dc.language.isoenen_US
dc.relation.ispartofBMC Blood Disorden_US
dc.rightsThe author(s) or copyright owner(s) irrevocably grant(s) to any third party, in advance and in perpetuity, the right to use, reproduce or disseminate the research article in its entirety or in part, in any format or medium, provided that no substantive errors are introduced in the process, proper attribution of authorship and correct citation details are given, and that the bibliographic details are not changed. If the article is reproduced or disseminated in part, this must be clearly and unequivocally indicated.
dc.titleA mutation in a functional Sp1 binding site of the telomerase RNA gene (hTERC) promoter in a patient with Paroxysmal Nocturnal Haemoglobinuria.en_US
dc.typeArticle
dc.identifier.doi10.1186/1471-2326-4-3en_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/15212690en_US
pubs.issue1en_US
pubs.notesNot knownen_US
pubs.organisational-group/Queen Mary University of London
pubs.organisational-group/Queen Mary University of London/Faculty of Medicine & Dentistry
pubs.organisational-group/Queen Mary University of London/Faculty of Medicine & Dentistry/Blizard Institute
pubs.organisational-group/Queen Mary University of London/Faculty of Medicine & Dentistry/Blizard Institute/Genomics and Child Health
pubs.organisational-group/Queen Mary University of London/REF
pubs.organisational-group/Queen Mary University of London/REF/REF - SMD - Blizard
pubs.organisational-group/Queen Mary University of London/REF/REF - UoA 01
pubs.publication-statusPublished onlineen_US
pubs.volume4en_US
dcterms.dateAccepted2004-06-22en_US


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