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

Keith, W.N. et al. (2004) A mutation in a functional Sp1 binding site of the telomerase RNA gene (hTERC) promoter in a patient with Paroxysmal Nocturnal Haemoglobinuria. BMC Blood Disorders, 4(3), (doi: 10.1186/1471-2326-4-3)



Publisher's URL: http://dx.doi.org/10.1186/1471-2326-4-3


Background<br/><br/> 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.<br/><br/> Methods<br/><br/> 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.<br/><br/> Results<br/><br/> 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.<br/><br/> Conclusions<br/><br/> 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.

Item Type:Articles
Additional Information:This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL
Glasgow Author(s) Enlighten ID:Keith, Professor Nicol and Bilsland, Dr Alan
Authors: Keith, W.N., Vulliamy, T., Zhao, J., Ar, C., Erzik, C., Bilsland, A., Ulku, B., Marrone, A., Mason, P.J., Bessler, M., Serakinci, N., and Dokal, I.
Subjects:R Medicine > RB Pathology
R Medicine > RC Internal medicine
Q Science > QH Natural history > QH426 Genetics
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:BMC Blood Disorders
Publisher:BioMed Central Ltd.
Copyright Holders:© 2004 Keith et al; licensee BioMed Central Ltd.
First Published:First published in BMC Blood Disorders 4:3
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.

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