Mutations in the Gene PRRT2 Cause Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions

SummaryParoxysmal 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.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► The gene PRRT2 is mutated in PKD/IC patients ► PRRT2 is expressed in the CNS and interacts with SNAP25 ► sTruncated forms of PRRT2 are not expressed in cultured cells ► Wild-type PRRT2 is in neuronal processes of transfected rat hippocampal neurons