IDENTIFICATION OF THE SECOND LAFORA PROGRESSIVE MYOCLONUS EPILEPSY GENE
Abstract number :
D.02
Submission category :
Year :
2003
Submission ID :
3602
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Elayne M. Chan, Edwin J. Young, Iulia Munteanu-Oprea, Leonarda Ianzano, Stephen W. Scherer, Berge A. Minassian Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, ON, Canada; Molecular and Medical Genetics, The University of
Lafora disease (LD) is a progressive myoclonus epilepsy with onset in teenage years. It is an autosomal recessive disorder and one of the most severe forms of juvenile epilepsy. Symptoms include myoclonus, ictal visual hallucinations and other seizures paralleled by a severe cognitive decline and death within 10 years of onset. Mutations in the [italic]EPM2A [/italic]gene are present in approximately 70% of LD families, and the gene in the remaining families was so far unknown. The [italic]EPM2A [/italic]encoded protein, named laforin, contains a carbohydrate binding motif and a dual-specificity phosphatase domain. Recently we identified the first interactor of laforin, a novel protein of unknown function named EPM2AIP1. Despite these findings, the pathway involving laforin and EPM2AIP1 and their involvement in the onset of LD is still unclear.
One approach we took to identify protein components that are involved in the same pathway was to search for the second LD gene by genetic mapping studies. A genome-wide linkage scan was performed using four families of a French-Canadian [lsquo]isolate[rsquo] that do not segregate any [italic]EPM2A [/italic]mutations.
Two-point lod scores at one marker gave a lod score of 2.84 at a recombination fraction of [theta] = 0. Additional markers in the region were genotyped and all affected individuals were homozygous across a 2.2 Mb region for a 7-marker haplotype that was not present in 100 ethnically matched controls. Additional families were included in the study and genotyped at markers in the critical interval. One family further refined the region to a 0.84 Mb region based on loss of homozygosity at 4 of the 7 markers that define the critical interval. Four genes in this region were examined for sequence changes. Mutations in one gene were identified in 21 families of various origins including the French-Canadian cluster. The mutations include 6 missense changes and 5 deletions.
We will describe the identification of the second Lafora disease gene and the characterization of its protein product.
[Supported by: We would like to thank the many clinicians for providing patient DNA especially Eva Andermann, Antonio V. Delgado-Escueta, and Guy A. Rouleau. This work was funded by the Canadian Institute of Health Research (CIHR).]