Expanded Repeat in Canine Epilepsy

Lohi, Hannes; Young, Edwin J.; Fitzmaurice, Susan N.; Rusbridge, Clare; Chan, Elayne M.; Vervoort, Mike; Turnbull, Julie; Zhao, Xiao Chu; Ianzano, Leonarda; Paterson, Andrew D.; Sutter, Nathan B.; Ostrander, Elaine A.; André, Catherine; Shelton, G. Diane; Ackerley, Cameron; Scherer, Stephen W.; Minassian, Berge A.

doi:10.1126/science.1102832

Cited by 157 publications

(180 citation statements)

References 4 publications

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“…A canine model for LD is also known with defects in the NHLRC1 gene [Lohi et al, 2005b]. Nearly 5% of purebred miniature wirehaired dachshunds in the United Kingdom are known to suffer from LD.…”

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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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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“…Recent studies have brought advances in understanding the genetics of breed development 15 and the availability of ever higher resolution maps [16][17][18][19][20][21] . These have led to the mapping of disease loci for a variety of diseases including metabolic disorders 22,23 , blindness [24][25][26][27][28] , cancer 29,30 neurologic disorders 31,32 , hip dysplasia 33 epilepsy 34 , as well as several morphologic traits 35,36 . In addition, the advancement of a framework for how to study complex canine traits 37 has led to deepening of our knowledge about the organization of the canine genome 38,39 and how it relates to morphological variation between breeds.…”

Section: Introductionmentioning

confidence: 99%

Finding cardiovascular disease genes in the dog

Parker

Meurs

Ostrander

2006

Journal of Veterinary Cardiology

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Recent advances in canine genomics are changing the landscape of veterinary biology, and by default, veterinary medicine. No longer are clinicians locked into traditional methods of diagnoses and therapy. Rather major advances in canine genetics and genomics from the past five years are now changing the way the veterinarian of the 21 st century practices medicine.First, the availability of a dense genome map gives canine genetics a much needed foothold in comparative medicine, allowing advances made in human and mouse genetics to be applied to companion animals. Second, the recently released 7.5x whole genome sequence of the dog is facilitating the identification of hereditary disease genes. Finally, development of genetic tools for rapid screening of families and populations at risk for inherited disease means that the cost of identifying and testing for disease loci will significantly decrease in coming years.Out of these advances will come major changes in companion animal diagnostics and therapy. Clinicians will be able to offer their clients genetic testing and counseling for a myriad of disorders. Such advances are certain to generate healthier and more long lived dogs, improving quality of life for owner and pet alike. The clinician of the 21 st century, therefore, faces incredible opportunities as well as challenges in the management of genetic disease. In this review we summarize recent findings in canine genomics and discuss their application to the study of canine cardiac health.

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“…Thus, identification of the third player, and cellular substrates for laforin and malin would be important milestones in unravelling the physiological pathway defective in LD. With the availability of LD animal models for both EPM2A and NHLRC1 gene defects (Ganesh et al 2002c;Lohi et al 2005b), the identification of additional players in LD will aid in the development of both drugs and treatments.…”

Section: Disease Mechanismmentioning

confidence: 99%

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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Expanded Repeat in Canine Epilepsy

Cited by 157 publications

References 4 publications

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

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

Finding cardiovascular disease genes in the dog

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

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