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. 2011 Dec;134(Pt 12):3493-3501.
doi: 10.1093/brain/awr289. Epub 2011 Nov 26.

Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias

Jun-Ling Wang  1 , Li Cao, Xun-Hua Li, Zheng-Mao Hu, Jia-Da Li, Jian-Guo Zhang, Yu Liang, San-A, Nan Li, Su-Qin Chen, Ji-Feng Guo, Hong Jiang, Lu Shen, Lan Zheng, Xiao Mao, Wei-Qian Yan, Ying Zhou, Yu-Ting Shi, San-Xi Ai, Mei-Zhi Dai, Peng Zhang, Kun Xia, Sheng-Di Chen, Bei-Sha Tang
Affiliations

Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias

Jun-Ling Wang et al. Brain. 2011 Dec.

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.

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Figures

Figure 1
Figure 1
Linkage analysis of Families A and B mapped the PKD to a region on chromosome 16p12.1-q12.1. The partial pedigrees of Families A and B were shown and haplotype analysis was indicated on chromosome 16 using 11 markers. The haplotype assumed to carry the disease allele is indicated with black bars. The haplotype with recombination event is indicated with black and white bars. Subjects in Families A and B are identified by the Arabic numerals above the symbol; and the Roman numerals denote the generations. Open symbols = unaffected; filled symbols = affected; symbols with a diagonal line = deceased subjects; squares = male; circles = female; arrow = the proband; minus = wild-type allele; plus = mutant allele; NG = not genotyped.
Figure 2
Figure 2
Pedigrees of three additional families with PKD. Subjects in Families C–E were identified by the Arabic numerals above the symbol, and Roman numerals denote the generation. Symbols are the same as in Fig. 1.
Figure 3
Figure 3
Mutations of the PRRT2 gene. (A) Sanger sequencing of codons 214–220 of PRRT2 in a wild-type (WT) subject and (B) the c.649_650InsC (p.P217fsX7) mutation. The mutation results in a frame-shift, which generates different sequences starting at position 217 and introduces a premature stop codon at position 224. (C) Sanger sequencing of codons 162–164 of PRRT2 in a wild-type subject (left) and an affected subject (right) with c.487C>T (p.Q163X) mutation. (D) Sanger sequencing of codons 265–267 of PRRT2 in a wild-type subject (left) and an affected subject (right) with c.796C>T p.R266W mutation. The mutant sites are indicated by red triangles in B–D. (E) Schematic diagram of PRRT2 gene and wild-type or mutant PRRT2 protein. The three mutations identified in this study are indicated with arrows. PRRT2 gene consists of four exons. PRRT2 protein has two domains: two low complexity segments followed by two transmembrane segments. All three mutations are located upstream of the coding region of the first transmembrane segment of PRRT2 protein. (F) The diagram of chromosome 16 indicating the relative position of PKD locus. The minimal linkage interval of PKD is 19.16 cM between D16S401 and D16S2623 on chromosome 16p12.1-q12.1. The PRRT2 position is indicated with a red triangle.
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