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Paroxysmal kinesigenic dyskinesias is a paroxysmal movement disorder characterized by recurrent, brief attacks of abnormal involuntary movements induced by sudden voluntary movements. Although several loci, including the pericentromeric region of chromosome 16, have been linked to paroxysmal kinesigenic dyskinesias, the causative gene has not yet been identified. Here, we identified proline-rich transmembrane protein 2 (PRRT2) as a causative gene of paroxysmal kinesigenic dyskinesias by using a combination of exome sequencing and linkage analysis. Genetic linkage mapping with 11 markers that encompassed the pericentromeric of chromosome 16 was performed in 27 members of two families with autosomal dominant paroxysmal kinesigenic dyskinesias. Then, the whole-exome sequencing was performed in three patients from these two families. By combining the defined linkage region (16p12.1-q12.1) and the results of exome sequencing, we identified an insertion mutation c.649_650InsC (p.P217fsX7) in one family and a nonsense mutation c.487C>T (p.Q163X) in another family. To confirm our findings, we sequenced the exons and flanking introns of PRRT2 in another three families with paroxysmal kinesigenic dyskinesias. The c.649_650InsC (p.P217fsX7) mutation was identified in two of these families, whereas a missense mutation, c.796C>T (R266W), was identified in another family with paroxysmal kinesigenic dyskinesias. All of these mutations completely co-segregated with the phenotype in each family. None of these mutations was identified in 500 normal unaffected individuals of matched geographical ancestry. Thus, we have identified PRRT2 as the first causative gene of paroxysmal kinesigenic dyskinesias, warranting further investigations to understand the pathogenesis of this disorder. [ABSTRACT FROM AUTHOR]

SNCA is a pathogenic gene identified in rare familial PD, and over-expression of SNCA was suggested in the pathogenesis of familial and sporadic PD. Rep1 polymorphism of SNCA was associated with susceptibility to sporadic PD and SNCA expression in intro and in vivo. Hypomethylation in SNCA intron-1 was associated with increased SNCA expression and was observed in postmortem brains of patients with sporadic PD. We studied the methylation status of SNCA intron-1, SNCA mRNA levels and Rep1 genotypes in PBMCs of 100 sporadic PD patients and 95 controls and explored the relationship between DNA methylation, mRNA expression and Rep1 genotypes. Hypomethylation of SNCA intron-1 was detected in PBMCs of PD patients, and DNA methylation levels were associated with Rep1 polymorphism. The shorter allele was associated with higher level of SNCA intron-1 methylation, and genotypes carrying the shorter allele showed significantly higher methylation level of SNCA intron-1 than genotypes carrying the longer allele. However, SNCA mRNA levels were not associated with disease status, Rep1 polymorphism or DNA methylation of SNCA intron-1 in our study., (Copyright © 2013 Elsevier B.V. All rights reserved.)