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A mutation in a functional Sp1 binding site of the telomerase RNA gene (hTERC) promoter in a patient with Paroxysmal Nocturnal Haemoglobinuria

W Nicol Keith1, Tom Vulliamy2, Jiangqin Zhao1, Cem Ar3, Can Erzik4, Alan Bilsland1, Birsen Ulku3, Anna Marrone2, Philip J Mason25*, Monica Bessler5, Nedime Serakinci6 and Inderjeet Dokal2

Author Affiliations

1 Cancer Research UK, Department of Medical Oncology, Cancer Research UK Beatson Laboratories, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK

2 Department of Haematology-Division of Investigative Science, Imperial College London, Hammersmith Hospital, London, UK

3 Department of Haematology, Cerrahpasa Medical Faculty, Istanbul University, Turkey

4 Medical Faculty, Marmara University, Turkey

5 Department of Internal Medicine, Division of Hematology, Washington University School of Medicine, St.Louis, MO, 63110, USA

6 Department of Human Genetics, Bartholin Building, University of Aarhus, Universitetsparken, 8000 Aarhus C, Denmark

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BMC Blood Disorders 2004, 4:3  doi:10.1186/1471-2326-4-3

Published: 22 June 2004



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.


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.


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.


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.