Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
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 (57)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Ganesh, S.
Right arrow Articles by Yamakawa, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ganesh, S.
Right arrow Articles by Yamakawa, K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, 2000, Vol. 9, No. 15 2251-2261
© 2000 Oxford University Press

Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes

Subramaniam Ganesh, Kishan Lal Agarwala, Kazunori Ueda2, Takumi Akagi1, Keiko Shoda, Takeo Usui2, Tsutomu Hashikawa1, Hiroyuki Osada2, Antonio V. Delgado-Escueta3 and Kazuhiro Yamakawa+

Laboratory for Neurogenetics and 1Neural Architecture Laboratory, Brain Science Institute and 2Antibiotics Laboratory, The Institute of Physical and Chemical Research (RIKEN), 2–1 Hirosawa, Wako-shi, Saitama 351-0198, Japan and 3Epilepsy Genomics Laboratories, Comprehensive Epilepsy Program, UCLA School of Medicine and VA GLAHS West Los Angeles Medical Center, Los Angeles, CA, USA

The progressive myoclonus epilepsy of Lafora type is an autosomal recessive disorder caused by mutations in the EPM2A gene. EPM2A is predicted to encode a putative tyrosine phosphatase protein, named laforin, whose full sequence has not yet been reported. In order to understand the function of the EPM2A gene, we isolated a full-length cDNA, raised an antibody and characterized its protein product. The full-length clone predicts a 38 kDa laforin that was very close to the size detected in transfected cells. Recombinant laforin was able to hydrolyze phosphotyrosine as well as phosphoserine/threonine substrates, demonstrating that laforin is an active dual-specificity phosphatase. Biochemical, immunofluorescence and electron microscopic studies on the full-length laforin expressed in HeLa cells revealed that laforin is a cytoplasmic protein associated with polyribosomes, possibly through a conformation-dependent protein–protein interaction. We analyzed the intracellular targeting of two laforin mutants with missense mutations. Expression of both mutants resulted in ubiquitin-positive perinuclear aggregates suggesting that they were misfolded proteins targeted for degradation. Our results suggest that laforin is involved in translational regulation and that protein misfolding may be one of the molecular bases of the Lafora disease phenotype caused by missense mutations in the EPM2A gene.

+ To whom correspondence should be addressed. Tel: +81 48 467 9703; Fax: +81 48 462 4796; Email: yamakawa@brain.riken.go.jp


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
 Hum Mol GenetHome page
Y. Liu, Y. Wang, C. Wu, Y. Liu, and P. Zheng
Deletions and missense mutations of EPM2A exacerbate unfolded protein response and apoptosis of neuronal cells induced by endoplasm reticulum stress
Hum. Mol. Genet., July 15, 2009; 18(14): 2622 - 2631.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
P. Garyali, P. Siwach, P. K. Singh, R. Puri, S. Mittal, S. Sengupta, R. Parihar, and S. Ganesh
The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system
Hum. Mol. Genet., February 15, 2009; 18(4): 688 - 700.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
R. Liu, L. Wang, C. Chen, Y. Liu, P. Zhou, Y. Wang, X. Wang, J. Turnbull, B. A. Minassian, Y. Liu, et al.
Laforin Negatively Regulates Cell Cycle Progression through Glycogen Synthase Kinase 3{beta}-Dependent Mechanisms
Mol. Cell. Biol., December 1, 2008; 28(23): 7236 - 7244.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
D. Dubey and S. Ganesh
Modulation of functional properties of laforin phosphatase by alternative splicing reveals a novel mechanism for the EPM2A gene in Lafora progressive myoclonus epilepsy
Hum. Mol. Genet., October 1, 2008; 17(19): 3010 - 3020.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
A. Cheng, M. Zhang, M. S. Gentry, C. A. Worby, J. E. Dixon, and A. R. Saltiel
A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori's disease
Genes & Dev., October 1, 2007; 21(19): 2399 - 2409.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
M. S. Gentry, R. H. Dowen III, C. A. Worby, S. Mattoo, J. R. Ecker, and J. E. Dixon
The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease
J. Cell Biol., July 24, 2007; 178(3): 477 - 488.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Mittal, D. Dubey, K. Yamakawa, and S. Ganesh
Lafora disease proteins malin and laforin are recruited to aggresomes in response to proteasomal impairment
Hum. Mol. Genet., April 1, 2007; 16(7): 753 - 762.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
H. Lohi, J. Turnbull, X. C. Zhao, S. Pullenayegum, L. Ianzano, M. Yahyaoui, M. A. Mikati, N. P. Quinn, S. Franceschetti, F. Zara, et al.
Genetic diagnosis in Lafora disease: Genotype-phenotype correlations and diagnostic pitfalls
Neurology, March 27, 2007; 68(13): 996 - 1001.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Liu, Y. Wang, C. Wu, Y. Liu, and P. Zheng
Dimerization of Laforin Is Required for Its Optimal Phosphatase Activity, Regulation of GSK3beta Phosphorylation, and Wnt Signaling
J. Biol. Chem., November 17, 2006; 281(46): 34768 - 34774.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. A. Worby, M. S. Gentry, and J. E. Dixon
Laforin, a Dual Specificity Phosphatase That Dephosphorylates Complex Carbohydrates
J. Biol. Chem., October 13, 2006; 281(41): 30412 - 30418.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
S Singh, I Sethi, S Francheschetti, C Riggio, G Avanzini, K Yamakawa, A V Delgado-Escueta, and S Ganesh
Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora's progressive myoclonic epilepsy.
J. Med. Genet., September 1, 2006; 43(9): e48 - e48.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
H. Lohi, L. Ianzano, X.-C. Zhao, E. M. Chan, J. Turnbull, S. W. Scherer, C. A. Ackerley, and B. A. Minassian
Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy
Hum. Mol. Genet., September 15, 2005; 14(18): 2727 - 2736.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. S. Gentry, C. A. Worby, and J. E. Dixon
From The Cover: Insights into Lafora disease: Malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin
PNAS, June 14, 2005; 102(24): 8501 - 8506.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
E. M. Chan, C. A. Ackerley, H. Lohi, L. Ianzano, M. A. Cortez, P. Shannon, S. W. Scherer, and B. A. Minassian
Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy
Hum. Mol. Genet., June 1, 2004; 13(11): 1117 - 1129.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. E. Fernandez-Sanchez, O. Criado-Garcia, K. E. Heath, B. Garcia-Fojeda, I. Medrano-Fernandez, P. Gomez-Garre, P. Sanz, J. M. Serratosa, and S. Rodriguez de Cordoba
Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation
Hum. Mol. Genet., December 1, 2003; 12(23): 3161 - 3171.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Ganesh, N. Tsurutani, T. Suzuki, K. Ueda, K. L. Agarwala, H. Osada, A. V. Delgado-Escueta, and K. Yamakawa
The Lafora disease gene product laforin interacts with HIRIP5, a phylogenetically conserved protein containing a NifU-like domain
Hum. Mol. Genet., September 15, 2003; 12(18): 2359 - 2368.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
E M Chan, D E Bulman, A D Paterson, J Turnbull, E Andermann, F Andermann, G A Rouleau, A V Delgado-Escueta, S W Scherer, and B A Minassian
Genetic mapping of a new Lafora progressive myoclonus epilepsy locus (EPM2B) on 6p22
J. Med. Genet., September 1, 2003; 40(9): 671 - 675.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
I. Taylor, I. E. Scheffer, and S. F. Berkovic
Occipital epilepsies: identification of specific and newly recognized syndromes
Brain, April 1, 2003; 126(4): 753 - 769.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
R. Di Giaimo, M. Riccio, S. Santi, C. Galeotti, D. C. Ambrosetti, and M. Melli
New insights into the molecular basis of progressive myoclonus epilepsy: a multiprotein complex with cystatin B
Hum. Mol. Genet., November 1, 2002; 11(23): 2941 - 2950.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Ganesh, A. V. Delgado-Escueta, T. Sakamoto, M. R. Avila, J. Machado-Salas, Y. Hoshii, T. Akagi, H. Gomi, T. Suzuki, K. Amano, et al.
Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice
Hum. Mol. Genet., May 16, 2002; 11(11): 1251 - 1262.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
S. Ganesh, A. V. Delgado-Escueta, T. Suzuki, S. Francheschetti, C. Riggio, G. Avanzini, A. Rabinowicz, S. Bohlega, J. Bailey, M. E. Alonso, et al.
Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype
Hum. Mol. Genet., May 16, 2002; 11(11): 1263 - 1271.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Wang, J. A. Stuckey, M. J. Wishart, and J. E. Dixon
A Unique Carbohydrate Binding Domain Targets the Lafora Disease Phosphatase to Glycogen
J. Biol. Chem., January 18, 2002; 277(4): 2377 - 2380.
[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.