PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects.
PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects.
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DOI：
10.18632/oncotarget.9258
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Tsai JW
中科院分区：
文献类型：
--
作者：
Liu YT;Nian FS;Chou WJ;Tai CY;Kwan SY;Chen C;Kuo PW;Lin PH;Chen CY;Huang CW;Lee YC;Soong BW;Tsai JW
富含脯氨酸的跨膜蛋白2(PRRT2)基因突变可引起多种神经系统疾病，包括阵发性运动性运动障碍(PKD)、智力低下和癫痫。此前，在台湾人群中发现了7个与PKD相关的PRRT2杂合突变：P91QfsX、E199X、S202HfsX、R217PfsX、R217EfsX、R240X和R308C。本研究旨在探讨这些PRRT2基因突变的致病机制。我们首次通过突触膜分离和免疫组织化学染色证明Prrt2定位于突触前膜和突触后膜，并与SNAP25有密切的空间联系。我们的结果显示，六个截断的Prrt2突变体积累在细胞质中，因此无法靶向细胞膜；R308C错义突变体显著降低了蛋白质表达，表明这些突变产生了功能丧失效应。利用宫内电穿孔技术将shRNA导入大脑皮层神经元，我们进一步发现，体内下调Prrt2的表达导致胚胎发育期间神经元迁移延迟，出生后突触密度显著下降。这些病理效应和新的致病机制可能与PRRT2相关疾病的严重临床症状有关。
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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影响因子：
5.5
作者：
CHRISTENSEN, BN;TEUBL, WP
通讯作者：
TEUBL, WP
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影响因子：
2.6
作者：
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通讯作者：
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影响因子：
30.8
作者：
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通讯作者：
Wu, Zhi-Ying
影响因子：
2.5
作者：
CHRISTENSEN, BN
通讯作者：
CHRISTENSEN, BN
影响因子：
2.7
作者：
Saito, T;Nakatsuji, N
通讯作者：
Nakatsuji, N