Abstract
Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is an episodic movement disorder with autosomal-dominant inheritance and high penetrance, but the causative genetic mutation is unknown. We have now identified four truncating mutations involving the gene PRRT2 in the vast majority (24/25) of well-characterized families with PKD/IC. PRRT2 truncating mutations were also detected in 28 of 78 additional families. PRRT2 encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the t-SNARE, SNAP25. PRRT2 localizes to axons but not to dendritic processes in primary neuronal culture, and mutants associated with PKD/IC lead to dramatically reduced PRRT2 levels, leading ultimately to neuronal hyperexcitability that manifests in vivo as PKD/IC.
Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Amino Acid Sequence
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Animals
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Central Nervous System / metabolism
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Chromosome Segregation / genetics
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DNA Copy Number Variations / genetics
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Dystonia / complications*
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Dystonia / genetics*
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Female
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Genome, Human / genetics
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HEK293 Cells
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Humans
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Male
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Membrane Proteins / chemistry
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Membrane Proteins / genetics*
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Mice
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Molecular Sequence Data
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Mutant Proteins / metabolism
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Mutation / genetics*
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / genetics*
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Pedigree
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Phenotype
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Protein Binding / genetics
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Rats
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Seizures / complications*
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Seizures / genetics*
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Sequence Alignment
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Sequence Analysis, DNA
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Species Specificity
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Synaptosomal-Associated Protein 25 / metabolism
Substances
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Membrane Proteins
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Mutant Proteins
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Nerve Tissue Proteins
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PRRT2 protein, human
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Synaptosomal-Associated Protein 25
Supplementary concepts
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Familial paroxysmal dystonia