Founder Effect with Variable Age at Onset in Arab Families with Lafora Disease and <i>EPM2A</i> Mutation

Gómez-Abad, C.; Afawi, Zaid; Korczyn, Amos D.; Misk, Adel; Shalev, Stavit A.; Spiegel, Ronen; Lerman‐Sagie, Tally; Lev, Dorit; Kron, Katherine L.; Gómez-Garre, Pilar; Serratosa, Joan; Berkovic, Samuel F.

doi:10.1111/j.1528-1167.2007.01004.x

Cited by 21 publications

(17 citation statements)

References 11 publications

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“…The exon-3 homozygous deletion observed for the EPM2A gene in 4 independent LD families suggests that this mutation could be novel to the Indian populations. Larger deletions in the EPM2A gene have been observed in many populations (American, Arabic and Caucasian) but all such deletions were restricted to the exon 2 or the exon 1-2 combined regions (Minassian et al, 1998;Serratosa et al, 1999;Minassian et al, 2000;Gomez-Garre et al, 2000;Ganesh et al, 2002;Ganesh et al, 2006;Gomez-Abad et al, 2007). The present study suggests that such deletions need not be restricted to a few exons of the gene.…”

Section: Discussioncontrasting

confidence: 43%

“…Interestingly, the spectrum of mutations and the associated gene appears to differ among LD populations: While EPM2A is more often mutated in the Spanish population, it is defects in the NHLRC1 gene that are the common cause for LD in Italian population . Large deletions in the EPM2A gene appear to be common among the LD patients from the Middle East (Gomez-Abad et al, 2007). However, no systematic study has been carried out to evaluate mutational spectrum and locus heterogeneity for LD in Indian population.…”

Section: Introductionmentioning

confidence: 95%

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Lafora disease in the Indian population:EPM2A andNHLRC1 gene mutations and their impact on subcellular localization of laforin and malin

et al. 2008

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Lafora disease (LD) is a fatal form of teenage-onset autosomal recessive progressive myoclonus epilepsy. LD is more common among geographic isolates and in populations with a higher rate of consanguinity. Mutations in two genes, EPM2A encoding laforin phosphatase, and NHLRC1 encoding malin ubiquitin ligase, have been shown to cause the LD. We describe here a systematic analysis of the EPM2A and the NHLRC1 gene sequences in 20 LD families from the Indian population. We identified 12 distinct mutations in 15 LD families. The identified novel mutations include 4 missense mutations (K140N, L310W, N148Y, and E210 K) and a deletion of exon 3 for EPM2A, and 4 missense mutations (S22R, L279P, L279P, and L126P) and a single base-pair insertional mutation (612insT) for NHLRC1. The EPM2A gene is known to encode two laforin isoforms having distinct carboxyl termini; a major isoform localized in the cytoplasm, and a minor isoform that targeted the nucleus. We show here that the effect of the EPM2A gene mutation L310W was limited to the cytoplasmic isoform of laforin, and altered its subcellular localization. We have also analyzed the impact of NHLRC1 mutations on the subcellular localization of malin. Of the 6 distinct mutants tested, three targeted the nucleus, one formed perinuclear aggregates, and two did not show any significant difference in the subcellular localization as compared to the wild-type malin. Our results suggest that the altered subcellular localization of mutant proteins of the EPM2A and NHLRC1 genes could be one of the molecular bases of the LD phenotype.

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Section: Discussioncontrasting

confidence: 43%

Section: Introductionmentioning

confidence: 95%

Lafora disease in the Indian population:EPM2A andNHLRC1 gene mutations and their impact on subcellular localization of laforin and malin

et al. 2008

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“…Indeed, heterogeneity in the phenotype has been document within an ethnic group of patients that shared the same mutation in EPM2A [Gomez-Abad et al, 2007]. However, positive correlations have also been observed for a subphenotype of LD and the mutations in the exon 1 of the EPM2A gene [Annesi et al, 2004;Ganesh et al, 2002b].…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

“…document severe liver failure in one of the two siblings genetically diagnosed to have LD (EPM2A gene defect), suggesting a role for modifier genes for the clinical expression of symptoms outside the nervous system in LD [Gomez-Garre et al, 2007].…”

Section: Clinical and Diagnostic Relevancementioning

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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“…For examples, several of the NHLRC1 patients studied showed severe form LD 19 or a late onset LD, 20 and not all EPM2A patients with exon 1 mutations showed an early onset of the LD symptoms. 17,18 Intriguingly, a founder effect mutation for EPM2A in Arab families showed variable age at onset for LD, 21 suggesting that a specific …”

mentioning

confidence: 99%

Phenotype variations in Lafora progressive myoclonus epilepsy: possible involvement of genetic modifiers?

Singh

Ganesh

2012

J Hum Genet

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Lafora progressive myoclonus epilepsy, also known as Lafora disease (LD), is the most severe and fatal form of progressive myoclonus epilepsy with its typical onset during the late childhood or early adolescence. LD is characterized by recurrent epileptic seizures and progressive decline in intellectual function. LD can be caused by defects in any of the two known genes and the clinical features of these two genetic groups are almost identical. The past one decade has witnessed considerable success in identifying the LD genes, their mutations, the cellular functions of gene products and on molecular basis of LD. Here, we briefly review the current literature on the phenotype variations, on possible presence of genetic modifiers, and candidate modifiers as targets for therapeutic interventions in LD. Keywords: epilepsy; genetic modifiers; glycogen metabolism; Mendelian disorders; neurodegeneration; protein-protein interaction Progressive myoclonus epilepsies (PMEs) are a group of rare genetic disorders characterized by myoclonic seizures and progressive neurological deterioration. 1 Among the progressive myoclonus epilepsies, Lafora type epilepsy, also known as Lafora disease (LD), is unique because clinical variations are not that common, yet the disease can be caused by defects in any of the three chromosomal loci (6q24, 6p22.3 and one unknown locus). [1][2][3][4] Two genes for LD have already been identified, 3 and evidences for the presence of a third locus are ample. 3,5 Clinical course of the LD is characterized by the onset of myoclonus, grand mal, tonic clonic and absence seizures during the adolescence or in the late childhood. Cognitive decline, dystharthia and ataxia are noted at 11-17 years. 1 Patients are usually bedridden at around 20 years and then on survival requires respiratory assistance. 1,6 Pathologically, LD is characterized by the presence of pathognomonic intra-neuronal cytoplasmic inclusions called the Lafora bodies. 4,6 These inclusions stain positive for the periodic acid-Schiff reagent, suggesting the presence of a large amount of carbohydrate. Biochemical studies demonstrate that these inclusions are made up of abnormally lesser branched and hyperphosphorylated glycogenmoieties. 7,8 Besides the Lafora bodies, neurodegenerative changes are also seen. 9 Nonetheless, the cause and consequence of Lafora bodies in LD pathogenesis are yet to be unequivocally established.The two genes known for LD have been extensively characterized. These are the EPM2A and NHLRC1 genes, coding for a protein phosphatase (named laforin) and an E3 ubiquitin ligase (named malin), respectively. 3 Laforin and malin interact with each other and as a complex participate in diverse cellular pathways, including the glycogen metabolism, ubiquitin-proteasome system and in heat shock response, 3,10-13 and therefore defects in these processes are thought underlie LD. 3 A number of disease-causing mutations, more than 100 of them, are known in EPM2A and NHLRC1, and several studies have looked at possible genotype-phe...

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Founder Effect with Variable Age at Onset in Arab Families with Lafora Disease and EPM2A Mutation

Cited by 21 publications

References 11 publications

Lafora disease in the Indian population:EPM2A andNHLRC1 gene mutations and their impact on subcellular localization of laforin and malin

Lafora disease in the Indian population:EPM2A andNHLRC1 gene mutations and their impact on subcellular localization of laforin and malin

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

Phenotype variations in Lafora progressive myoclonus epilepsy: possible involvement of genetic modifiers?

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