Lafora progressive myoclonus epilepsy mutation database-EPM2A and NHLRC1 (EMP2B) genes

Ianzano, Leonarda; Zhang, Junjun; Chan, Elayne M.; Zhao, Xiao Chu; Lohi, Hannes; Scherer, Stephen W.; Minassian, Berge A.

doi:10.1002/humu.9376

Cited by 52 publications

(44 citation statements)

References 22 publications

(28 reference statements)

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“…Mutations in malin account for more than 50% of reported cases of LD (30,31). Recently it was shown that malin and laforin recruited to aggresomes under proteasome impairment and the malin-laforin complex degrade misfolded proteins (21).…”

Section: Discussionmentioning

confidence: 99%

Co-chaperone CHIP Stabilizes Aggregate-prone Malin, a Ubiquitin Ligase Mutated in Lafora Disease

Rao

Sharma²,

Maity

et al. 2010

Journal of Biological Chemistry

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Lafora disease (LD) is an autosomal recessive neurodegenerative disorder caused by mutation in either the dual specificity phosphatase laforin or ubiquitin ligase malin. A pathological hallmark of LD is the accumulation of cytoplasmic polyglucosan inclusions commonly known as Lafora bodies in both neuronal and non-neuronal tissues. How mutations in these two proteins cause disease pathogenesis is not well understood. Malin interacts with laforin and recruits to aggresomes upon proteasome inhibition and was shown to degrade misfolded proteins. Here we report that malin is spontaneously misfolded and tends to be aggregated, degraded by proteasomes, and forms not only aggresomes but also other cytoplasmic and nuclear aggregates in all transfected cells upon proteasomal inhibition. Malin also interacts with Hsp70. Several disease-causing mutants of malin are comparatively more unstable than wild type and form aggregates in most transfected cells even without the inhibition of proteasome function. These cytoplasmic and nuclear aggregates are immunoreactive to ubiquitin and 20 S proteasome. Interestingly, progressive proteasomal dysfunction and cell death is also most frequently observed in the mutant malin-overexpressed cells compared with the wild-type counterpart. Finally, we demonstrate that the co-chaperone carboxyl terminus of the Hsc70-interacting protein (CHIP) stabilizes malin by modulating the activity of Hsp70. All together, our results suggest that malin is unstable, and the aggregate-prone protein and co-chaperone CHIP can modulate its stability.

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Section: Discussionmentioning

confidence: 99%

Co-chaperone CHIP Stabilizes Aggregate-prone Malin, a Ubiquitin Ligase Mutated in Lafora Disease

Rao

Sharma²,

Maity

et al. 2010

Journal of Biological Chemistry

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“…Since then, several groups have identified mutations in the EPM2A and NHLRC1 genes in LD families from diverse populations. Although a database for the LD mutations was reported in the literature [Ianzano et al, 2005] (http://projects.tcag.ca/lafora/), neither it is [Ganesh et al, 2003], R5 and EPM2AIP1 require the full-length laforin for interaction Ferná ndez-Sá nchez et al, Ianzano et al, 2003] (interacting domains identified by thin lines). Laforin-laforin and laforin-malin interactions (identified by double headed arrows) have also been reported [Dubey and Ganesh., 2008;Ferná ndez-Sá nchez et al, 2003;Gentry et al, 2005;Liu et al, 2006].…”

Section: Mutational Spectrum Of Epm2a and Nhlrc1 Genesmentioning

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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“…To date, mutations in two genes have been shown to account for ϳ90% of LD cases. Approximately 60% of LD cases can be attributed to mutations in the EPM2A (epilepsy progressive myoclonus type 2A) gene, which encodes, by sequence, a dual specificity protein phosphatase named laforin (12,15,16). Laforin also contains a highly conserved carbohydrate-binding module subtype 20 (17) that interacts with glycogen and the polyglucosan found in patients with LD (18,19).…”

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confidence: 99%

Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease

Tagliabracci

Girard

Segvich

et al. 2008

Journal of Biological Chemistry

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Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual specificity protein phosphatase family that is able to release the small amount of covalent phosphate normally present in glycogen. In studies of Epm2a ؊/؊ mice that lack laforin, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. At three months, glycogen metabolism remained essentially normal, even though the phosphorylation of glycogen has increased 4-fold and causes altered physical properties of the polysaccharide. By 9 months, the glycogen has overaccumulated by 3-fold, has become somewhat more phosphorylated, but, more notably, is now poorly branched, is insoluble in water, and has acquired an abnormal morphology visible by electron microscopy. These glycogen molecules have a tendency to aggregate and can be recovered in the pellet after low speed centrifugation of tissue extracts. The aggregation requires the phosphorylation of glycogen. The aggregrated glycogen sequesters glycogen synthase but not other glycogen metabolizing enzymes. We propose that laforin functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen.Glycogen is a branched polymer of glucose that acts as a repository of energy used in times of need (1). Liver and skeletal muscle contain the two largest deposits in mammals, but heart, brain, adipose, as well as many other tissues synthesize the polymer. Polymerization occurs via ␣-1,4-glycosidic linkages between glucose residues, with branch points introduced by ␣-1,6-glycosidic linkages. The frequency of branching determines the topology of glycogen and distinguishes it from the carbohydrate moiety of starch (2). A unique three-dimensional structure of glycogen cannot be determined experimentally because of the polydispersity of the molecule, but a widely accepted model of its structure has been proposed (3). Glycogen is composed of successive layers, or tiers, of glucose residues; a full size molecule consists of 12 tiers, with M r ϭ ϳ10 7 and a diameter of ϳ40 nm (4). Glycogen has been reported to contain small amounts of covalently linked phosphate, on the order of 0.064% by weight or 0.121% mol/mol (5-7). The mechanism by which the phosphate is introduced remains unclear. One suggestion (5) has been the existence of a glucose-1-phosphate transferase that would form C1-C6 bridging phosphodiesters, but this enzyme has not been further defined at the molecular level. In plant amylopectin, C1 and C3 phosphomonoesters have been shown to be formed by dikinase enzymes (8), but...

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Lafora progressive myoclonus epilepsy mutation database-EPM2A and NHLRC1 (EMP2B) genes

Cited by 52 publications

References 22 publications

Co-chaperone CHIP Stabilizes Aggregate-prone Malin, a Ubiquitin Ligase Mutated in Lafora Disease

Co-chaperone CHIP Stabilizes Aggregate-prone Malin, a Ubiquitin Ligase Mutated in Lafora Disease

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

Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease

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