Skip Navigation



Human Molecular Genetics Advance Access published online on July 21, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi254
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
14/17/2501    most recent
ddi254v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Gallagher, P. G.
Right arrow Articles by Bodine, D. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gallagher, P. G.
Right arrow Articles by Bodine, D. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved
Received June 3, 2005
Revised July 8, 2005
Accepted July 8, 2005

Article

A Dinucleotide Deletion in the Ankyrin Promoter Alters Gene Expression, Transcription Initiation and TFIID Complex Formation in Hereditary Spherocytosis

Patrick G. Gallagher 1*, Douglas G. Nilson 2, Clara Wong 3, Jessica L. Weisbein 2, Lisa J. Garrett-Beal 2, Stephan W. Eber 4, and David M. Bodine 2

1 Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208064, New Haven, CT 06520-8064, USA
2 Hematopoiesis Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
3 Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA
4 Universitäts-Kinderklinik Zürich, Zurich, Switzerland CH-8032

* To whom correspondence should be addressed.
Patrick G. Gallagher, E-mail: patrick.gallagher{at}yale.edu


  Abstract

Ankyrin defects are the most common cause of hereditary spherocytosis (HS). In some HS patients, mutations in the ankyrin promoter have been hypothesized to lead to decreased ankyrin mRNA synthesis. The ankyrin erythroid promoter is a member of the most common class of mammalian promoters which lack conserved TATA, initiator, or other promoter cis elements, have high G + C content, functional Sp1 binding sites, and multiple transcription initiation sites. We identified a novel ankyrin gene promoter mutation, a TG deletion adjacent to a transcription initiation site, in a patient with ankyrin-linked HS and analyzed its effects on ankyrin expression. In vitro, the mutant promoter directed decreased levels of gene expression, altered transcription initiation site utilization, and exhibited defective TATA-binding protein (TBP) binding and TFIID complex formation. In a transgenic mouse model, the mutant ankyrin promoter led to abnormalities in gene expression, including decreased expression of a reporter gene and altered transcription initiation site utilization. These data indicate that the mutation alters ankyrin gene transcription and contributes to the HS phenotype by decreasing ankyrin gene synthesis via disruption of TFIID complex interactions with the ankyrin core promoter. These studies support the model that in promoters that lack conserved cis elements, the TFIID complex directs preinitiation complex formation at specific sites in core promoter DNA and provide the first evidence that disruption of TBP binding and TFIID complex formation in this type of promoter leads to alterations in start site utilization, decreased gene expression, and a disease phenotype in vivo.

Keywords: Hereditary spherocytosis; ankyrin; promoter; mutation; transcription.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.