Mutations in PRRT2 Gene Cause Episodic Diseases: From Paroxysmal Dyskinesia to Episodic Ataxia and Hemiplegic Migraine

Recently, exome sequencing has identified mutations in the proline-rich transmembrane protein (PRRT2) as being responsible for the condition paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC), an episodic disease where sufferers experience involuntary movements triggered by sudden voluntary movements. As episodic neurological disorders often exist in a spectrum, we sequenced this gene in cohorts of patients with familial hemiplegic migraine (FHM) and episodic ataxia (EA) as well as PKD. Exons and splice junctions of PRRT2 were sequenced using Sanger sequencing in 58 family probands/sporadic individuals with PKD/IC, 182 with EA and 128 with HM and 561 UK and 96 Asian controls. PRRT2 genetic mutations were identified in 28 of 58 (48%) the PKD/IC cases, as well as one EA case and one FHM case. This is first time this gene has been linked to another disease. Six different mutations were found, four of which were novel. These were a mixture of nonsense and missense mutations. The most frequent mutation found was the p.R217Pfs*8 insertion (24 cases). This mutation leads to a truncated protein, which has been shown in HEK cells to have a very low expression; therefore it is likely that this disease is caused by haploinsufficiency. We expressed a similar novel truncation mutant (p.L171Lfs*3) in HEK cells, with the expectation that we will see a similar result. We also expressed a novel missense variant (G305W) in HEK cells, and we will investigate the effects that this mutation has on the expression and localisation of PRRT2, as it is likely that if this variant is pathogenic, the mechanism will be different from the truncation mutations. This study expanded the phenotypic range associated with PRRT2 to include EA and FHM, as well as investigating the hypothesis that multiple molecular mechanisms could be responsible for PKD