This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow An erratum has been published
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
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 Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jiang, Z.
Right arrow Articles by Wu, J. Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jiang, Z.
Right arrow Articles by Wu, J. Y.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, June 2000, p. 4036-4048, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Aberrant Splicing of tau Pre-mRNA Caused by Intronic Mutations Associated with the Inherited Dementia Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17

Zhihong Jiang,1 Jocelyn Cote,1 Jennifer M. Kwon,2 Alison M. Goate,3 and Jane Y. Wu1,4,*

Department of Pediatrics,1 Department of Neurology,2 Departments of Psychiatry & Genetics,3 and Department of Molecular Biology and Pharmacology,4 Washington University School of Medicine, St. Louis, Missouri 63110

Received 4 November 1999/Returned for modification 8 December 1999/Accepted 1 March 2000

Frontotemporal dementia accounts for a significant fraction of dementia cases. Frontotemporal dementia with parkinsonism linked to chromosome 17 is associated with either exonic or intronic mutations in the tau gene. This highlights the involvement of aberrant pre-mRNA splicing in the pathogenesis of neurodegenerative disorders. Little is known about the molecular mechanisms of the splicing defects underlying these diseases. To establish a model system for studying the role of pre-mRNA splicing in neurodegenerative diseases, we have constructed a tau minigene that reproduces tau alternative splicing in both cultured cells and in vitro biochemical assays. We demonstrate that mutations in a nonconserved intronic region of the human tau gene lead to increased splicing between exon 10 and exon 11. Systematic biochemical analyses indicate the importance of U1 snRNP and, to a lesser extent, U6 snRNP in differentially recognizing wild-type versus intron mutant tau pre-mRNAs. Gel mobility shift assays with purified U1 snRNP and oligonucleotide-directed RNase H cleavage experiments support the idea that the intronic mutations destabilize a stem-loop structure that sequesters the 5' splice site downstream of exon 10 in tau pre-mRNA, leading to increases in U1 snRNP binding and in splicing between exon 10 and exon 11. Thus, mutations in nonconserved intronic regions that increase rather than decrease alternative splicing can be an important pathogenic mechanism for the development of human diseases.

* Corresponding author. Mailing address: Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110. Phone: (314) 454-2081. Fax: (314) 454-2388. E-mail: jwu{at}molecool.wustl.edu.

Molecular and Cellular Biology, June 2000, p. 4036-4048, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Rodriguez-Martin, T., Anthony, K., Garcia-Blanco, M. A., Mansfield, S. G., Anderton, B. H., Gallo, J.-M. (2009). Correction of tau mis-splicing caused by FTDP-17 MAPT mutations by spliceosome-mediated RNA trans-splicing. Hum Mol Genet 18: 3266-3273 [Abstract] [Full Text]  
  • Wolfe, M. S. (2009). Tau Mutations in Neurodegenerative Diseases. J. Biol. Chem. 284: 6021-6025 [Abstract] [Full Text]  
  • Abbink, T. E. M., Berkhout, B. (2008). RNA Structure Modulates Splicing Efficiency at the Human Immunodeficiency Virus Type 1 Major Splice Donor. J. Virol. 82: 3090-3098 [Abstract] [Full Text]  
  • Donahue, C. P., Ni, J., Rozners, E., Glicksman, M. A., Wolfe, M. S. (2007). Identification of Tau Stem Loop RNA Stabilizers. J Biomol Screen 12: 789-799 [Abstract]  
  • Wu, J. Y., Kar, A., Kuo, D., Yu, B., Havlioglu, N. (2006). SRp54 (SFRS11), a Regulator for tau Exon 10 Alternative Splicing Identified by an Expression Cloning Strategy.. Mol. Cell. Biol. 26: 6739-6747 [Abstract] [Full Text]  
  • Kar, A., Havlioglu, N., Tarn, W.-Y., Wu, J. Y. (2006). RBM4 Interacts with an Intronic Element and Stimulates Tau Exon 10 Inclusion. J. Biol. Chem. 281: 24479-24488 [Abstract] [Full Text]  
  • Donahue, C. P., Muratore, C., Wu, J. Y., Kosik, K. S., Wolfe, M. S. (2006). Stabilization of the Tau Exon 10 Stem Loop Alters Pre-mRNA Splicing. J. Biol. Chem. 281: 23302-23306 [Abstract] [Full Text]  
  • Su, Z., Wang, J., Yu, J., Huang, X., Gu, X. (2006). Evolution of alternative splicing after gene duplication. Genome Res 16: 182-189 [Abstract] [Full Text]  
  • Baralle, D, Baralle, M (2005). Splicing in action: assessing disease causing sequence changes. J. Med. Genet. 42: 737-748 [Abstract] [Full Text]  
  • Yuan, L., Kawada, M., Havlioglu, N., Tang, H., Wu, J. Y. (2005). Mutations in PRPF31 Inhibit Pre-mRNA Splicing of Rhodopsin Gene and Cause Apoptosis of Retinal Cells. J. Neurosci. 25: 748-757 [Abstract] [Full Text]  
  • Buratti, E., Baralle, F. E. (2004). Influence of RNA Secondary Structure on the Pre-mRNA Splicing Process. Mol. Cell. Biol. 24: 10505-10514 [Full Text]  
  • Buratti, E., Muro, A. F., Giombi, M., Gherbassi, D., Iaconcig, A., Baralle, F. E. (2004). RNA Folding Affects the Recruitment of SR Proteins by Mouse and Human Polypurinic Enhancer Elements in the Fibronectin EDA Exon. Mol. Cell. Biol. 24: 1387-1400 [Abstract] [Full Text]  
  • Kondo, S., Yamamoto, N., Murakami, T., Okumura, M., Mayeda, A., Imaizumi, K. (2004). Tra2{beta}, SF2/ASF and SRp30c modulate the function of an exonic splicing enhancer in exon 10 of tau pre-mRNA. GENES CELLS 9: 121-130 [Abstract] [Full Text]  
  • Jiang, Z., Tang, H., Havlioglu, N., Zhang, X., Stamm, S., Yan, R., Wu, J. Y. (2003). Mutations in Tau Gene Exon 10 Associated with FTDP-17 Alter the Activity of an Exonic Splicing Enhancer to Interact with Tra2{beta}. J. Biol. Chem. 278: 18997-19007 [Abstract] [Full Text]  
  • Sobrido, M.-J., Miller, B. L., Havlioglu, N., Zhukareva, V., Jiang, Z., Nasreddine, Z. S., Lee, V. M.-Y., Chow, T. W., Wilhelmsen, K. C., Cummings, J. L., Wu, J. Y., Geschwind, D. H. (2003). Novel Tau Polymorphisms, Tau Haplotypes, and Splicing in Familial and Sporadic Frontotemporal Dementia. Arch Neurol 60: 698-702 [Abstract] [Full Text]  
  • Muh, S. J., Hovhannisyan, R. H., Carstens, R. P. (2002). A Non-sequence-specific Double-stranded RNA Structural Element Regulates Splicing of Two Mutually Exclusive Exons of Fibroblast Growth Factor Receptor 2 (FGFR2). J. Biol. Chem. 277: 50143-50154 [Abstract] [Full Text]  
  • Kan, Z., States, D., Gish, W. (2002). Selecting for Functional Alternative Splices in ESTs. Genome Res 12: 1837-1845 [Abstract] [Full Text]  
  • Honig, A., Auboeuf, D., Parker, M. M., O'Malley, B. W., Berget, S. M. (2002). Regulation of Alternative Splicing by the ATP-Dependent DEAD-Box RNA Helicase p72. Mol. Cell. Biol. 22: 5698-5707 [Abstract] [Full Text]  
  • D'Souza, I., Schellenberg, G. D. (2002). tau Exon 10 Expression Involves a Bipartite Intron 10 Regulatory Sequence and Weak 5' and 3' Splice Sites. J. Biol. Chem. 277: 26587-26599 [Abstract] [Full Text]  
  • Cote, J., Dupuis, S., Wu, J. Y. (2001). Polypyrimidine Track-binding Protein Binding Downstream of Caspase-2 Alternative Exon 9 Represses Its Inclusion. J. Biol. Chem. 276: 8535-8543 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»