Progressive myoclonus epilepsy with polyglucosans (Lafora disease)

Chan, Elayne M.; Omer, Salah; Ahmed, Mushtaq; Bridges, Leslie; Bennett, Christopher; Scherer, Stephen W.; Minassian, Berge A.

doi:10.1212/01.wnl.0000133215.65836.03

Cited by 84 publications

(60 citation statements)

References 9 publications

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“…While patients with mutations in EPM2A and NHLRC1 express similar clinical manifestations, patients with EPM2A-associated LD seem to have a more severe clinical course because NHLRC1-defective patients tend to live longer than those with EPM2A defects (Gomez-Abad et al 2005). At least one other, still unknown, gene also causes LD; Chan et al (2004a) G15fs S25P E28K W32G W32fs A37fs Q55X W60X G75fs G79fs D82fs F84L Y86X F88L K90fs R91P R108C Y112fs E138X W165X R171H T187A T194I E224I G240S R241X H253fs N263fs N267fs T274fs G279S Q293L Y294N P301L Q319fs ------------------------------------- to demonstrate the presence of a third locus for LD. This has also been supported by an independent study (Singh et al 2005).…”

Section: Locus Heterogeneity In Ldmentioning

confidence: 99%

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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%

“…To rule out the potential existence of mutations in the regulatory regions of these two genes, Chan et al (2004a) genotyped a consanguineous LD family with multiple affected children and excluded the involvement of the EPM2A and NHLRC1 loci. Thus, there appears to be at least one additional, as yet unknown, genetic locus for LD.…”

Section: Epm2cmentioning

confidence: 99%

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

et al. 2005

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“…Defects in EPM2A and NHLRC1 account for around 80% of the LD families that are screened for genetic lesions. In the remaining families, a role for a third gene is suggested [Chan et al, 2004b]. The EPM2A gene encodes a dual-specificity protein phosphatase, called laforin, that localizes in the rough endoplasmic reticulum [Ganesh et al, 2000].…”

Section: Introductionmentioning

confidence: 99%

Lafora progressive myoclonus epilepsy: A meta-analysis of reported mutations in the first decade following the discovery of theEPM2AandNHLRC1genes

2009

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Lafora disease (LD) is an autosomal recessive and fatal form of progressive myoclonus epilepsy. LD patients manifest myoclonus and tonic-clonic seizures, visual hallucinations, and progressive neurologic deterioration beginning at 12 to 15 years of age. The two genes known to be associated with LD are EPM2A and NHLRC1. Mutations in at least one other as yet unknown gene also cause LD. The EMP2A encodes a protein phosphatase and NHLRC1 encodes an ubiquitin ligase. These two proteins interact with each other and, as a complex, are thought to regulate critical neuronal functions. Nearly 100 distinct mutations have been discovered in the two genes in over 200 independent LD families. Nearly half of them are missense mutations, and the deletion mutations account for one-quarter. Several reports have provided functional data for the mutant proteins and a few also provide genotype-phenotype correlations. In this review we provide an update on the spectrum of EPM2A and NHLRC1 mutations, and discuss their distribution in the patient population, genotype-phenotype correlations, and on the possible effect of disease mutations on the cellular functions of LD proteins.

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“…Mutations in EPM2A are responsible for Ϸ48% of LD cases (14). Of the remaining cases, Ϸ40% are the result of mutations in EPM2B (14,15). To date, the molecular mechanisms underlying LD in patients harboring mutations in either EPM2A or EPM2B have not been defined.…”

mentioning

confidence: 99%

Insights into Lafora disease: Malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin

Gentry

Worby

Dixon

2005

Proc. Natl. Acad. Sci. U.S.A.

225

256

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Lafora disease (LD) is a fatal form of progressive myoclonus epilepsy caused by recessive mutations in either a gene encoding a dual-specificity phosphatase, known as laforin, or a recently identified gene encoding the protein known as malin. Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation. Missense mutations in malin that are present in LD patients abolish its ability to polyubiquitinate and signal the degradation of laforin. Our results demonstrate that laforin is a physiologic substrate of malin, and we propose possible models to explain how recessive mutations in either malin or laforin result in LD. Furthermore, these data distinguish malin as an E3 Ub ligase whose activity is necessary to prevent a neurodegenerative disease that involves formation of nonproteinacious inclusion bodies.progressive myoclonus epilepsy ͉ phosphatase ͉ neurodegenerative disease

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Progressive myoclonus epilepsy with polyglucosans (Lafora disease)

Cited by 84 publications

References 9 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

Lafora progressive myoclonus epilepsy: A meta-analysis of reported mutations in the first decade following the discovery of theEPM2AandNHLRC1genes

Insights into Lafora disease: Malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin

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