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Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia


Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal movement disorder and is often misdiagnosed clinically as epilepsy. Using whole-exome sequencing followed by Sanger sequencing, we identified three truncating mutations within PRRT2 (NM_145239.2) in eight Han Chinese families with histories of paroxysmal kinesigenic dyskinesia: c.514_517delTCTG (p.Ser172Argfs*3) in one family, c.649dupC (p.Arg217Profs*8) in six families and c.972delA (p.Val325Serfs*12) in one family. These truncating mutations co-segregated exactly with the disease in these families and were not observed in 1,000 control subjects of matched ancestry. PRRT2 is a newly discovered gene consisting of four exons encoding the proline-rich transmembrane protein 2, which encompasses 340 amino acids and contains two predicted transmembrane domains. PRRT2 is highly expressed in the developing nervous system, and a truncating mutation alters the subcellular localization of the PRRT2 protein. The function of PRRT2 and its role in paroxysmal kinesigenic dyskinesia should be further investigated.

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Figure 1: The pedigrees of the eight families affected by paroxysmal kinesigenic dyskinesia included in the present study.
Figure 2: PRRT2 protein domain structure.
Figure 3: Expression of PRRT2 in the mouse brain.
Figure 4: Truncated PPRT2 has altered cellular localization.

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The authors sincerely thank the participants for their help and willingness to take part in this study. The authors also thank the Beijing Genomics Institute (BGI)-Shenzhen for assistance in the analysis of exome sequence data. This work was supported by a grant from the National Natural Science Foundation (China; 81125009 to Z.-Y.W.) and a grant from Huashan Hospital for the special professorship of Fudan University (to Z.-Y.W.) and by a key program of scientific research of Fujian Medical University (2009D064 to N.W.).

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N.W. and Z.-Y.W. planned the project. Z.-Q.X., J.X., N.W. and Z.-Y.W. conceived of and designed the study. W.-J.C., Yu Lin, Yi Lin, S.-X.M., N.W. and Z.-Y.W. performed the sample collection. W.-J.C., Yu Lin, W.W., W.N., J.H., Y.-F.C., Q.-J.Z. and H.-F.L. performed sequence analysis. J.-F.X. and Z.-Y.W. performed linkage and haplotype analyses. Z.-Q.X., G.-H.T. and S.-L.G. performed the expression analysis. W.-J.C., Z.-Q.X., J.X., N.W. and Z.-Y.W. analyzed the data. W.-J.C., Z.-Q.X. and Z.-Y.W. wrote the manuscript, and J.X. and Z.-Y.W. revised it.

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Correspondence to Ning Wang or Zhi-Ying Wu.

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The authors declare no competing financial interests.

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Chen, WJ., Lin, Y., Xiong, ZQ. et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 43, 1252–1255 (2011).

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