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Mutations of proline‐rich transmembrane protein‐2 and paroxysmal kinesigenic dyskinesia in Taiwan

Several mutations in the gene of proline-rich transmembrane protein 2 (PRRT2) have been identified as the causes of paroxysmal kinesigenic dyskinesia (PKD). PRRT2 is a small gene that contains 4 exons and encodes a 340-aminoacid protein with 2 transmembrane domains. It is expressed predominantly in the brain. In the current study, we examined the whole PRRT2 gene, and we observed novel truncation PRRT2 mutations that co-segregated with PKD phenotypes among the Taiwanese population. Patients were recruited in the Department of Neurology, Chang Gung Memorial Hospital (CGMH), Linkou Medical Center. In total, 53 participants were ascertained for the genetic analysis. Patients were included when the following inclusion criteria were fulfilled: (1) age of onset between 1 and 20 years, (2) an identified kinesigenic trigger for the attacks and short duration of attacks (<1 minute), (3) no loss of consciousness or pain during attacks, and (4) control of attacks with antiepileptic drugs. Two hundred controls were included to confirm the mutations that we identified. All participants provided written informed consent to the study, and the protocol was approved by the Institutional Review Boards of CGMH. We sequenced the whole gene, including its 500 base pairs upstream of the promoter, in 53 participants (8 patients with sporadic PKD, 33 patients with familial PKD, and 12 unaffected family members). We analyze heterozygous base-calling fluorescence chromatogram data using comparisons with reference sequences using the Mixed Sequence Reader, as previously reported. The clinical information and the PRRT2 gene sequencing results are summarized in Table 1. The age of onset in these patients ranged from 1 to 19 years (mean 6 standard deviation, 11.8 6 4.3 years). We identified 3 mutations among 24 familial patients (69.7%) and 1 sporadic case (12.5%). In addition to the c.649dupC truncation, we identified 2 novel mutations, including c.601_604delCACT/p.S202HfsX26 and c.529G>T/p.E177* in 2 different families. All 3 of these mutations were within exon 2 and caused frameshifts with premature stop codons. We observed that these mutations co-segregated with the clinical phenotypes, whereas none of the unaffected individuals had the identified mutations. A nonsynonymous substitution at exon 2, c.412C>G, which leads to p.P138A, was identified in another sporadic patient. Among the 200 controls, we did not find any of the truncation mutations; however, we observed that 30 controls had c.412C>G/p.P138A, which was confirmed by thymine and adenine (TA) cloning and sequencing. These results suggested that c.412C>G is a common variant rather than a mutation among the Taiwanese population. Using the Affymetrix SNP-Array 6.0 (Affymetrix, Tokyo, Japan), we identified a common 209-kb-long haplotype segment (rs3764276 to rs12917712, chromosome 16: 29673203– 29882490), which was adjacent to the c.649dupC, in all 7 families and in the patient with sporadic disease who carried this mutation. In conclusion, we identified PRRT2 as the main causative gene for PKD among the Taiwanese population. In addition to the most common mutation (c.649dupC/p.R217PfsX8), we identified 2 novel truncation mutations, including c.601_604delCACT/p.S202HfsX26 and c.529G>T/p.E177*. Nonsynonymous substitution c.412C>G is a common variant in Taiwan.