title: Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias.
abstract: 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.
authors: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China.
authors: Jun-Ling
authors: JL
authors: Wang
authors: Li
authors: L
authors: Cao
authors: Xun-Hua
authors: XH
authors: Li
authors: Zheng-Mao
authors: ZM
authors: Hu
authors: Jia-Da
authors: JD
authors: Li
authors: Jian-Guo
authors: JG
authors: Zhang
authors: Yu
authors: Y
authors: Liang
authors: San-A
authors: Nan
authors: N
authors: Li
authors: Su-Qin
authors: SQ
authors: Chen
authors: Ji-Feng
authors: JF
authors: Guo
authors: Hong
authors: H
authors: Jiang
authors: Lu
authors: L
authors: Shen
authors: Lan
authors: L
authors: Zheng
authors: Xiao
authors: X
authors: Mao
authors: Wei-Qian
authors: WQ
authors: Yan
authors: Ying
authors: Y
authors: Zhou
authors: Yu-Ting
authors: YT
authors: Shi
authors: San-Xi
authors: SX
authors: Ai
authors: Mei-Zhi
authors: MZ
authors: Dai
authors: Peng
authors: P
authors: Zhang
authors: Kun
authors: K
authors: Xia
authors: Sheng-Di
authors: SD
authors: Chen
authors: Bei-Sha
authors: BS
authors: Tang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002819:Chorea / Q000235:genetics*; D002874:Chromosome Mapping; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D056426:Genetic Loci; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C569370:PRRT2 protein, human