Lafora Progressive Myoclonus Epilepsy: Narrowing the Chromosome 6q24 Locus by Recombinations and Homozygosities

Sainz, Jesús; Minassian, Berge A.; Serratosa, Joan; Gee, Melissa A.; Sakamoto, Lise M.; Iranmanesh, Reza; Bohlega, Saeed; Baumann, Robert J.; Ryan, Steve; Sparkes, Robert S.; Delgado‐Escueta, Antonio V.

doi:10.1086/301596

Cited by 27 publications

(13 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…3 Subsequent fine mapping studies revealed that the PCMT1 gene maps at least 1.7 megabases telomeric of the D6S311 marker, 3 which represents the telomeric border of the Lafora disease gene (35). Together, these studies exclude the PCMT1 gene as a culprit in Lafora's epilepsy.…”

Section: Discussionmentioning

confidence: 98%

Phenotypic Analysis of Seizure-prone Mice Lackingl-Isoaspartate (d-Aspartate)O-Methyltransferase

Kim

Lowenson

Clarke

et al. 1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

Within proteins and peptides, both L-asparaginyl and L-aspartyl residues spontaneously degrade, generating isomerized and racemized aspartyl residues. The enzyme protein L-isoaspartate (D-aspartate) O-methyltransferase (E.C. 2.1.1.77) initiates the conversion of Lisoaspartyl and D-aspartyl residues to normal L-aspartyl residues. This "repair" reaction helps to maintain proper protein conformation by preventing the accumulation of damaged proteins containing abnormal amino acid residues. Pcmt1-/-mice manifest two key phenotypes: a fatal seizure disorder and retarded growth. In this study, we characterized both phenotypes and demonstrated that they are linked. Continuous electroencephalogram monitoring of Pcmt1-/-mice revealed that abnormal cortical activity for ϳ50% of each 24-h period, even in mice that had no visible evidence of convulsions. The fatal seizure disorder in Pcmt1-/-mice can be mitigated but not eliminated by antiepileptic drugs. Interestingly, antiepileptic therapy normalized the growth of Pcmt1-/-mice, suggesting that the growth retardation is due to seizures rather than a global disturbance in growth at the cellular level. Consistent with this concept, the growth rate of Pcmt1-/-fibroblasts was indistinguishable from that of wild-type fibroblasts.Under physiological conditions, L-asparaginyl and L-aspartyl residues in polypeptides spontaneously degrade to L-and Disoaspartyl and D-aspartyl residues with half-times ranging from a few hours to hundreds of days (1-5). These abnormal residues can affect both the structure and function of polypeptides and may underlie a portion of the aging-related loss of cellular and tissue function (6 -9). However, many organisms have evolved a strategy for reversing at least some of this damage by an enzymatic methylation reaction that is targeted directly to peptides and proteins containing the major L-isoaspartyl degradation product. The widely distributed cytosolic protein L-isoaspartate (D-aspartate) O-methyltransferase, also termed protein carboxyl methyltransferase 1 (Pcmt1), 1 can initiate the conversion of L-isoaspartyl residues to L-aspartyl residues by forming the methyl ester of the L-isoaspartyl residue (10). This ester is then converted, in a nonenzymatic reaction, to an L-succinimidyl residue. Spontaneous hydrolysis of the L-succinimidyl residue produces either an L-aspartyl or an Lisoaspartyl residue. If an L-isoaspartyl residue is produced, additional rounds of methyl esterification, succinimide formation, and hydrolysis eventually convert it to an L-aspartyl residue.

show abstract

Section: Discussionmentioning

confidence: 98%

Phenotypic Analysis of Seizure-prone Mice Lackingl-Isoaspartate (d-Aspartate)O-Methyltransferase

Kim

Lowenson

Clarke

et al. 1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Thirty years after Schwarz established the diagnostic criteria for LD, his student, Delgado-Escueta and his previous postdoctoral fellows and present collaborators Serratosa, Minassian, and Ganesh used homozygosity mapping to identify [13], refine [14], and then bring the chromosome 6q24 locus of LD to one DNA marker [1]. Minassian and his team, in collaboration with the laboratory of Delgado-Escueta, were the first to identify mutations in EPM2A (laforin/dual specificity phosphatase) [1] and EPM2B (malin/E3 ubiquitin ligase) [3••] and elucidate some of their functions.…”

Section: History and Diagnosismentioning

confidence: 99%

Advances in Lafora progressive myoclonus epilepsy

Delgado‐Escueta

2007

Curr Neurol Neurosci Rep

Self Cite

View full text Add to dashboard Cite

Lafora progressive myoclonus epilepsy is an autosomal recessive, fatal, generalized polyglucosan storage disorder that occurs in childhood or adolescence with stimulus sensitive epilepsy (resting and action myoclonias, grand mal, and absence), dementia, ataxia and rapid neurologic deterioration. Mutations in EPM2A/laforin cause 58% of cases and mutations in EPM2B/malin cause 35% of cases. Accumulating evidence points to Lafora disease as primarily a disorder of cell death with impaired clearance of misfolded proteins, as shown by ubiquitin-positive aggresomes in HeLa cells transfected with mutated laforin, ubiquitin-positive polyglucosan inclusion bodies, and malin/E3 ubiquitin ligase polyubiquitination of laforin. How polyglucosan inclusion bodies accumulate is still a mystery. Polyglucosan accumulates hypothetically because of an overactive polyglucosan biosynthetic pathway or a breakdown in polyglucosan degradation. Five separate laboratories are looking for the biochemical pathways that connect laforin and malin to polyglucosan synthesis or degradation. A curative therapy for human Lafora disease with laforin replacement therapy using neutral pegylated immunoliposomes is being investigated.

show abstract

“…A gene for LD was localized to a 3 cM region on 6q24 (Serratosa et al 1995;Sainz et al 1997). 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.…”

Section: Locus Heterogeneity In Ldmentioning

confidence: 99%

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

et al. 2005

View full text Add to dashboard Cite

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.

show abstract

Lafora Progressive Myoclonus Epilepsy: Narrowing the Chromosome 6q24 Locus by Recombinations and Homozygosities

Cited by 27 publications

References 16 publications

Phenotypic Analysis of Seizure-prone Mice Lackingl-Isoaspartate (d-Aspartate)O-Methyltransferase

Phenotypic Analysis of Seizure-prone Mice Lackingl-Isoaspartate (d-Aspartate)O-Methyltransferase

Advances in Lafora progressive myoclonus epilepsy

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

Contact Info

Product

Resources

About