Nature Genetics
20, 171 - 174 (1998)
doi:10.1038/2470
Mutations in a gene encoding a novel protein tyrosine phosphatase cause
progressive myoclonus epilepsyBerge A. Minassian1, 2, Jeffrey R. Lee1, Jo-Anne Herbrick1, Jack Huizenga1, Sylvia Soder1, Andrew J. Mungall3, Ian Dunham3, Rebecca Gardner4, Chung-yan G. Fong5, Stirling Carpenter6, Laura Jardim7, P. Satishchandra8, Eva Andermann9, O. Carter Snead III2, Iscia Lopes-Cendes9, 10, Lap-Chee Tsui1, 11, Antonio V. Delgado-Escueta5, Guy A. Rouleau9, 10
& Stephen W. Scherer1, 111
Department of Genetics, Department of Paediatrics,
The Hospital for Sick Children, University of Toronto, Toronto
, Ontario, M5G 1X8, Canada. 2
Division of Neurology, Department of Paediatrics, The
Hospital for Sick Children, University of Toronto, Toronto,
Ontario, M5G 1X8, Canada. 3
Sanger Centre, Wellcome Trust Genome Campus,
Hinxton, Cambs. CB10 1SA, UK. 4
Wessex Regional Genetics Laboratory, Salisbury Health
Care NHS Trust, Salisbury District Hospital, Salisbury,
Wiltshire SP2 8BJ, UK. 5
California Comprehensive Epilepsy Program, UCLA School
of Medicine and West Los Angeles DVA Medical Center, Los Angeles
, California, USA. 6
Department of Pathology, The Toronto Hospital, University
of Toronto, Toronto, Ontario M5T 2S8,
Canada. 7
Medical Genetics Service, Hospital de Clinicas de Porto
Alegre, Porto Alegre RS 90035-003, Brazil
. 8
National Institute of Mental Health and Neurosciences,
Deemed University, Bangalore 560029, India
. 9
Department of Human Genetics, McGill University,
Montreal, Quebec, Canada. 10
Centre for Research in Neuroscience, Montreal General
Hospital Research Institute, Montreal, Quebec,
Canada. 11
Department of Molecular and Medical Genetics, University
of Toronto, Toronto, Ontario M5S 1A8,
Canada.
Correspondence should be addressed to Stephen W. Scherer steve@genet.sickkids.on.caLafora's disease (LD; OMIM 254780) is an autosomal recessive form of progressive
myoclonus epilepsy characterized by seizures and cumulative neurological deterioration.
Onset occurs during late childhood and usually results in death within ten
years of the first symptoms1,2. With few exceptions, patients
follow a homogeneous clinical course despite the existence of genetic heterogeneity
3. Biopsy of various tissues, including brain, revealed characteristic
polyglucosan inclusions called Lafora bodies4−8, which
suggested LD might be a generalized storage disease6,9. Using
a positional cloning approach, we have identified at chromosome 6q24 a novel
gene, EPM2A, that encodes a protein with consensus amino acid sequence
indicative of a protein tyrosine phosphatase (PTP). mRNA transcripts representing
alternatively spliced forms of EPM2A were found in every tissue examined,
including brain. Six distinct DNA sequence variations in EPM2A in nine
families, and one homozygous microdeletion in another family, have been found
to cosegregate with LD. These mutations are predicted to cause deleterious
effects in the putative protein product, named laforin, resulting in LD.
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