Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy

Minassian, Berge A.; Jeffrey, R. Lee; Herbrick, Jo Anne; Huizenga, Jack J.; Soder, Sylvia; Mungall, Andrew J.; Dunham, Ian; Gardner, R J; Fong, Chung Yan; Carpenter, Stirling; Jardim, Laura; Satishchandra, Parthasarathy; Andermann, Eva; Snead, O. Carter; Lopes-Cendes, Íscia; Tsui, Lap Chee; Delgado‐Escueta, Antonio V.; Rouleau, Guy A.; Scherer, Stephen W.

doi:10.1038/2470

Cited by 453 publications

(316 citation statements)

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“…Minassian et al (1998), Serratosa et al (1999) and Ganesh et al (2000) have independently cloned the EPM2A gene and showed that LD patients were homozygous or compound heterozygotes for presumably loss-of-functions mutations. The EPM2A gene encodes a protein phosphatase named laforin and is composed of four exons (Ganesh et al 2000).…”

Section: Locus Heterogeneity In Ldmentioning

confidence: 99%

Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsy

et al. 2005

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Lafora's disease (LD) is an autosomal recessive and fatal form of progressive myoclonus epilepsy with onset in late childhood or adolescence. LD is characterised by the presence of intracellular polyglucosan inclusions, called Lafora bodies, in tissues including the brain, liver and skin. Patients have progressive neurologic deterioration, leading to death within 10 years of onset. No preventive or curative treatment is available for LD. At least three genes underlie LD, of which two have been isolated and mutations characterised: EPM2A and NHLRC1. The EPM2A gene product laforin is a protein phosphatase while the NHLRC1 gene product malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Analyses of the structure and function of these gene products suggest defects in posttranslational modification of proteins as the common mechanism that leads to the formation of Lafora inclusion bodies, neurodegeneration and the epileptic phenotype of LD. In this review, we summarise the available information on the genetic basis of LD, and correlate these advances with the rapidly expanding information about the mechanisms of LD gained from studies on both cell biological and animal models. Finally, we also discuss a possible mechanism to explain the locus heterogeneity observed in LD.

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Section: Locus Heterogeneity In Ldmentioning

confidence: 99%

Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsy

et al. 2005

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“…EPM2A, encodes a protein, laforin, that belongs to the dual specificity protein phosphatase family [9]. Laforin also contains a functional polysaccharide binding domain [10][11][12] that binds preferentially to polyglucosan over glycogen [13].…”

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confidence: 99%

“…Laforin also contains a functional polysaccharide binding domain [10][11][12] that binds preferentially to polyglucosan over glycogen [13]. Some forty mutations have been identified throughout all four exons of the EPM2A gene (http://projects.tcag.ca/lafora/) [9,12,[14][15][16][17]. Most mutations cause a loss of phosphatase activity in recombinant laforin [11,18].…”

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confidence: 99%

Glycogen metabolism in tissues from a mouse model of Lafora disease

Wang

Lohi

Skurat

et al. 2007

Archives of Biochemistry and Biophysics

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Laforin, encoded by the EPM2A gene, by sequence is a member of the dual specificity protein phosphatase family. Mutations in the EPM2A gene account for around half of the cases of Lafora disease, an autosomal recessive neurodegenerative disorder, characterized by progressive myoclonus epilepsy. The hallmark of the disease is the presence of Lafora bodies, which contain polyglucosan, a poorly branched form of glycogen, in neurons, muscle and other tissues. Glycogen metabolizing enzymes were analyzed in a transgenic mouse over-expressing a dominant negative form of laforin that accumulates Lafora bodies in several tissues. Skeletal muscle glycogen was increased two-fold as was the total glycogen synthase protein. However, the −/+ glucose-6-P activity of glycogen synthase was decreased from 0.29 to 0.16. Branching enzyme activity was increased by 30%. Glycogen phosphorylase activity was unchanged. In whole brain, no differences in glycogen synthase or branching enzyme activities were found. Although there were significant differences in enzyme activities in muscle, the results do not support the hypothesis that Lafora body formation is caused by a major change in the balance between glycogen elongation and branching activities.Lafora disease is an autosomal recessive, progressive myoclonus epilepsy (OMIM #254780), with onset typically in teenagers followed by decline and death usually within ten years [1][2][3]. The disease is characterized by the presence of Lafora bodies, periodic acid-Schiff positive structures containing an abnormal form of glycogen, the branched polymer of glucose that serves as a stored form of glucose in many tissues. Although Lafora body formation in neurons is believed to account for the symptoms of the disease, the bodies are present in other tissues including liver, muscle and skin [4][5][6][7].Glycogen synthesis (Fig. 1) is mediated by glycogen synthase, which catalyzes formation of the predominant α-1,4-glycosidic linkage of the polymer and branching enzyme, which introduces the α-1,6-glycosidic branchpoints [8]. Degradation occurs in the cytosol through the action of glycogen phosphorylase and the debranching enzyme or alternatively in the lysosome via the activity of an α-glycosidase (acid maltase or GAA). In Lafora disease, a less ¶Correspondence to: Peter J. Roach, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5122, Phone 317 274-1582, FAX 317 274-4686, E-mail proach@iupui.edu. 1 Present address: Department of Medicine, University of California, San Diego, USA Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal di...

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“…EPM2A encodes a protein tyrosine phosphatase (LAFPTPase or laforin). 4,5 In spite of the remarkable allelic heterogeneity in the EPM2A gene, the R241stop mutation has been found in approximately 40% of Lafora disease patients with mutations in this gene. 6,7 The EPM2B gene (also called NHLRC1) encodes an E3 ubiquitin ligase (malin) and the most frequent mutation found is P69A.…”

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confidence: 99%

Hepatic disease as the first manifestation of progressive myoclonus epilepsy of Lafora

Gómez-Garre¹,

Gutierrez-Delicado²,

Gómez-Abad³

et al. 2007

Neurology

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Background: Lafora disease (LD; progressive myoclonus epilepsy type 2; EPM2) is an autosomal recessive disorder caused by mutations in the EPM2A and EPM2B genes. LD is characterized by the presence of strongly PAS-positive intracellular inclusions (Lafora bodies) in several tissues. Glycogen storage disease type IV (GSD-IV; Andersen disease) is an autosomal recessive disorder characterized by cirrhosis leading to severe liver failure. GSD-IV has been associated with mutations in the glycogen branching enzyme gene (GBE). Histopathologic changes of the liver in both diseases show an identical appearance, although cirrhosis has never been described in patients with LD. We report a LD family in which the proband presented severe liver failure at onset of the disease. Methods: Clinical histories, physical and neurologic examination, laboratory tests, EEGs, MRI of the brain, and liver or axillary skin biopsies were performed in the two affected siblings. The diagnosis was confirmed by molecular genetic analysis of the EPM2A, EPM2B, and GBE genes and loci. Results: During the first decade of life, abnormalities in liver function tests were detected in the two affected siblings. The proband's liver dysfunction was severe enough to require liver transplantation. Subsequently, both sibs developed LD. Mutation analysis of EPM2A revealed a homozygous Arg241stop mutation in both patients. Conclusions: This is the first description of severe hepatic dysfunction as the initial clinical manifestation of LD. The phenotypic differences between the two affected siblings suggest that modifier genes must condition clinical expression of the disease outside the CNS.

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Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy

Cited by 453 publications

References 21 publications

Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsy

Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsy

Glycogen metabolism in tissues from a mouse model of Lafora disease

Hepatic disease as the first manifestation of progressive myoclonus epilepsy of Lafora

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