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, Jin Wu Tsai*


研究成果: Article同行評審

42 引文 斯高帕斯(Scopus)


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.

頁(從 - 到)39184-39196
出版狀態Published - 2016


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