Genetic mapping of a new Lafora progressive myoclonus epilepsy locus (EPM2B) on 6p22

Chan, Elayne M.

doi:10.1136/jmg.40.9.671

Cited by 80 publications

(47 citation statements)

References 19 publications

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“…Missense mutation C26S is prevalent in the French-Canadian ethnic isolates and is yet to be detected in other populations (Chan et al 2003b). Interestingly, the chromosome 6p22 haplotype of these French-Canadian pedigrees did suggest a founder effect for the C26S mutation (Chan et al 2003a).…”

Section: Nhlrc1 (Epm2b)mentioning

confidence: 99%

“…The simplest explanation for this genetic heterogeneity is that another gene(s) in the same metabolic pathway is/are altered in LD families not linked to 6q24. Chan et al (2003a) mapped a second LD locus at 6p22, leading to the identification of a second LD gene named NHLRC1. NHLRC1 encodes malin, an E3 ubiquitin ligase with a RING finger domain and six NHL motifs (Fig.…”

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: Nhlrc1 (Epm2b)mentioning

confidence: 99%

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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“…Furthermore, haplotype analysis excluded the EPM2A locus as the primary cause for LD in these families, suggesting the presence of a second locus for LD . Recently, Chan et al (2003a) mapped a second LD locus, named EPM2B, at 6p22 based on a study of non-EPM2A LD families from the French Canadian population. Subsequently, the second LD gene, NHLRC1, was identified on the EPM2B locus (Chan et al 2003b).…”

Section: Introductionmentioning

confidence: 99%

Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population

et al. 2005

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Lafora disease (LD) is a rare autosomal recessive genetic disorder characterized by epilepsy, myoclonus, and progressive neurological deterioration. LD is caused by mutations in the EMP2A gene encoding a protein phosphatase. A second gene for LD, termed NHLRC1 and encoding a putative E3 ubiquitin ligase, was recently identified on chromosome 6p22. The LD is relatively common in southern Europe, the Middle East, and Southeast Asia. A few sporadic cases with typical LD phenotype have been reported from Japan; however, our earlier study failed to find EPM2A mutations in four Japanese families with LD. We recruited four new families from Japan and searched for mutations in EPM2A. All eight families were also screened for NHLRC1 mutations. We found five independent families having novel mutations in NHLRC1. Identified mutations include five missense mutations (p.I153M, p.C160R, p.W219R, p.D245N, and p.R253K) and a deletion mutation (c.897insA; p.S299fs13). We also found a family with a ten base pair deletion (c.822-832del10) in the coding region of EPM2A. In two families, no EPM2A or NHLRC1 mutation was found. Our study, in addition to documenting the genetic and molecular heterogeneity observed for LD, suggests that mutations in the NHLRC1 gene may be a common cause of LD in the Japanese population.

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“…100 Mutations in the Epm2b gene are also known to cause Lafora disease in humans. 30 Unlike human Lafora disease, in which signs are first seen in juveniles (teenagers), in MWD neurological signs in miniature wirehaired dachshunds appear in adulthood (6 to 9 years old), and some affected dogs live out their natural life span (over 15 years) (Fig. 18).…”

Section: Neuropilar Lesionsmentioning

confidence: 99%

Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases

et al. 2016

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According to the WHO, the proportion of people over 60 years is increasing and expected to reach 22% of total world's population in 2050. In parallel, recent animal demographic studies have shown that the life expectancy of pet dogs and cats is increasing. Brain aging is associated not only with molecular and morphological changes but also leads to different degrees of behavioral and cognitive dysfunction. Common age-related brain lesions in humans include brain atrophy, neuronal loss, amyloid plaques, cerebrovascular amyloid angiopathy, vascular mineralization, neurofibrillary tangles, meningeal osseous metaplasia, and accumulation of lipofuscin. In aging humans, the most common neurodegenerative disorder is Alzheimer's disease (AD), which progressively impairs cognition, behavior, and quality of life. Pathologic changes comparable to the lesions of AD are described in several other animal species, although their clinical significance and effect on cognitive function are poorly documented. This review describes the commonly reported age-associated neurologic lesions in domestic and laboratory animals and the relationship of these lesions to cognitive dysfunction. Also described are the comparative interspecies similarities and differences to AD and other human neurodegenerative diseases including Parkinson's disease and progressive supranuclear palsy, and the spontaneous and transgenic animal models of these diseases.

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Genetic mapping of a new Lafora progressive myoclonus epilepsy locus (EPM2B) on 6p22

Cited by 80 publications

References 19 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

Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population

Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases

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