Research Papers: Pathology:

PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects

Yo-Tsen Liu, Fang-Shin Nian, Wan-Ju Chou, Chin-Yin Tai, Shang-Yeong Kwan, Chien Chen, Pei-Wen Kuo, Po-Hsi Lin, Chin-Yi Chen, Chia-Wei Huang, Yi-Chung Lee, Bing-Wen Soong and Jin-Wu Tsai _

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Oncotarget. 2016; 7:39184-39196. https://doi.org/10.18632/oncotarget.9258

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Yo-Tsen Liu1,2, Fang-Shin Nian3,4, Wan-Ju Chou4, Chin-Yin Tai5, Shang-Yeong Kwan1,2, Chien Chen1,2, Pei-Wen Kuo4, Po-Hsi Lin2, Chin-Yi Chen6, Chia-Wei Huang4, Yi-Chung Lee1,2,7, Bing-Wen Soong1,2,7 and Jin-Wu Tsai4,7,8

1 Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan

2 Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan

3 Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan

4 Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan

5 Istitute of Pharmaceutics, Development Center for Biotechnology, New Taipei City, Taiwan

6 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan

7 Brain Research Center, National Yang-Ming University, Taipei, Taiwan

8 Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei, Taiwan

Correspondence to:

Jin-Wu Tsai, email:

Bing-Wen Soong, email:

Keywords: PRRT2, neuronal migration, synaptic development, paroxysmal kinesigenic dyskinesia (PKD), Taiwan, Pathology Section

Received: February 05, 2016 Accepted: April 26, 2016 Published: May 09, 2016


Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene cause a wide spectrum of neurological diseases, ranging from paroxysmal kinesigenic dyskinesia (PKD) to mental retardation and epilepsy. Previously, seven PKD-related PRRT2 heterozygous mutations were identified in the Taiwanese population: P91QfsX, E199X, S202HfsX, R217PfsX, R217EfsX, R240X and R308C. This study aimed to investigate the disease-causing mechanisms of these PRRT2 mutations. We first documented that Prrt2 was localized at the pre- and post-synaptic membranes with a close spatial association with SNAP25 by synaptic membrane fractionation and immunostaining of the rat neurons. Our results then revealed that the six truncating Prrt2 mutants were accumulated in the cytoplasm and thus failed to target to the cell membrane; the R308C missense mutant had significantly reduced protein expression, suggesting loss-of function effects generated by these mutations. Using in utero electroporation of shRNA into cortical neurons, we further found that knocking down Prrt2 expression in vivo resulted in a delay in neuronal migration during embryonic development and a marked decrease in synaptic density after birth. These pathologic effects and novel disease-causing mechanisms may contribute to the severe clinical symptoms in PRRT2–related diseases.

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