Skip Navigation


Human Molecular Genetics Advance Access originally published online on October 20, 2005
Human Molecular Genetics 2005 14(23):3661-3671; doi:10.1093/hmg/ddi394
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
14/23/3661    most recent
ddi394v1
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 ISI Web of Science
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 arrow Search for citing articles in:
ISI Web of Science (29)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Arocena, D. G.
Right arrow Articles by Hagerman, P. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Arocena, D. G.
Right arrow Articles by Hagerman, P. J.
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. For Permissions, please email: journals.permissions@oxfordjournals.org

Induction of inclusion formation and disruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cells

Dolores Garcia Arocena1,2, Christine K. Iwahashi1, Nelly Won1, Alexandra Beilina1, Anna L. Ludwig1, Flora Tassone1, Philip H. Schwartz3 and Paul J. Hagerman1,*

1Department of Biochemistry and Molecular Medicine, University of California Davis, School of Medicine, Davis, CA 95616, USA, 2Departamento de Genetica, Facultad de Medicina, UDELAR, Montevideo, Uruguay and 3Children's Hospital of Orange County Research Institute, Orange, CA 92868, USA

* To whom correspondence should be addressed at: Department of Biochemistry and Molecular Medicine, University of California Davis, School of Medicine, One Shields Avenue, Davis, CA 95616, USA. Tel: +1 5307547266; Fax: +1 5307547269; Email: pjhagerman{at}ucdavis.edu

Received August 2, 2005; Accepted October 13, 2005

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects some adult carriers of pre-mutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. FXTAS is thought to be caused by a toxic ‘gain-of-function’ of the expanded CGG-repeat FMR1 mRNA, which is found in the neuronal and astrocytic intranuclear inclusions associated with the disorder. Using a reporter construct with a FMR1 5' untranslated region harboring an expanded (premutation) CGG repeat, we have demonstrated that intranuclear inclusions can be formed in both primary neural progenitor cells and established neural cell lines. As with the inclusions found in post-mortem tissue, the inclusions induced by the expanded CGG repeat are {alpha}B-crystallin-positive; however, inclusions in culture are not associated with ubiquitin, indicating that incorporation of ubiquitinated proteins is a later event in the disease process. The absence of ubiquitinated proteins also argues against a model in which inclusion formation is due to a failure of the proteasomal degradative machinery. The presence of the expanded CGG repeat, as RNA, results in reduced cell viability as well as the disruption of the normal architecture of lamin A/C within the nucleus. This last observation, and the findings that lamin A/C is present in both the inclusions of FXTAS patients and the inclusions in cell culture, suggests that lamin A/C dysregulation may be a component of the pathogenesis of FXTAS; in particular, the Charcot–Marie–Tooth-type neuropathy associated with FXTAS may represent a functional laminopathy.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Nucleic Acids ResHome page
A. L. Ludwig, C. Raske, F. Tassone, D. Garcia-Arocena, J. W. Hershey, and P. J. Hagerman
Translation of the FMR1 mRNA is not influenced by AGG interruptions
Nucleic Acids Res., September 14, 2009; (2009) gkp713v1.
[Abstract] [Full Text] [PDF]

Home page
 Arch NeurolHome page
C. M. Greco, F. Tassone, D. Garcia-Arocena, N. Tartaglia, S. M. Coffey, T. K. Vartanian, J. A. Brunberg, P. J. Hagerman, and R. J. Hagerman
Clinical and Neuropathologic Findings in a Woman With the FMR1 Premutation and Multiple Sclerosis
Arch Neurol, August 1, 2008; 65(8): 1114 - 1116.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
K. Usdin
The biological effects of simple tandem repeats: Lessons from the repeat expansion diseases
Genome Res., July 1, 2008; 18(7): 1011 - 1019.
[Abstract] [Full Text] [PDF]

Home page
 Arch NeurolHome page
K. Soontarapornchai, R. Maselli, G. Fenton-Farrell, F. Tassone, P. J. Hagerman, D. Hessl, and R. J. Hagerman
Abnormal Nerve Conduction Features in Fragile X Premutation Carriers
Arch Neurol, April 1, 2008; 65(4): 495 - 498.
[Abstract] [Full Text] [PDF]

Home page
 Arch NeurolHome page
K. Amiri, R. J. Hagerman, and P. J. Hagerman
Fragile X Associated Tremor/Ataxia Syndrome: An Aging Face of the Fragile X Gene
Arch Neurol, January 1, 2008; 65(1): 19 - 25.
[Full Text] [PDF]

Home page
 Hum Mol GenetHome page
P. D. Ladd, L. E. Smith, N. A. Rabaia, J. M. Moore, S. A. Georges, R. S. Hansen, R. J. Hagerman, F. Tassone, S. J. Tapscott, and G. N. Filippova
An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals
Hum. Mol. Genet., December 15, 2007; 16(24): 3174 - 3187.
[Abstract] [Full Text] [PDF]

Home page
 RNAHome page
F. Tassone, A. Beilina, C. Carosi, S. Albertosi, C. Bagni, L. Li, K. Glover, D. Bentley, and P. J. Hagerman
Elevated FMR1 mRNA in premutation carriers is due to increased transcription
RNA, April 1, 2007; 13(4): 555 - 562.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
R. J. Osborne and C. A. Thornton
RNA-dominant diseases
Hum. Mol. Genet., October 15, 2006; 15(suppl_2): R162 - R169.
[Abstract] [Full Text] [PDF]


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.