Paroxysmal kinesigenic dyskinesia is an episodic movement disorder caused by dominant mutations in the proline-rich transmembrane protein PRRT2, with onset in childhood and typically with improvement or resolution by middle age. Mutations in the same gene may also cause benign infantile seizures, which begin in the first year of life and typically remit by the age of 2 years. Many details of PRRT2 function at the synapse, and the effects of mutations on neuronal excitability in the pathophysiology of epilepsy and dyskinesia, have emerged through the work of several groups over the last decade. However, the age dependence of the phenotypes has not been explored in detail in transgenic models. Here, we report our findings in heterozygous and homozygous Prrt2 knockout mice that recapitulate the age dependence of dyskinesia seen in the human disease. We show that Prrt2 deletion reduces the levels of synaptic proteins in a dose-dependent manner that is most pronounced at postnatal day 5 (P5), attenuates at P60, and disappears by P180. In a test for foot slippage while crossing a balance beam, transient loss of coordination was most pronounced at P60 and less prominent at age extremes. Slower traverse time was noted in homozygous knockout mice only, consistent with the ataxia seen in rare individuals with biallelic loss of function mutations in Prrt2. We thus identify three age-dependent phenotypic windows in the mouse model, which recapitulate the pattern seen in humans with PRRT2-related diseases.

阵发性运动源性运动障碍是一种由富含脯氨酸的跨膜蛋白 PRRT2 的显性突变引起的发作性运动障碍，在儿童时期发病，通常在中年时改善或消退。同一基因的突变也可能导致良性婴儿癫痫发作，这种癫痫发作始于出生后的第一年，通常在 2 岁时缓解。PRRT2 在突触中的功能的许多细节，以及突变对癫痫和运动障碍病理生理学中神经元兴奋性的影响，在过去十年中通过几个小组的工作已经出现。然而，在转基因模型中尚未详细探讨表型的年龄依赖性。在这里，我们报告了我们在杂合子和纯合子 Prrt2 敲除小鼠中的发现，这些小鼠概括了人类疾病中运动障碍的年龄依赖性。我们显示 Prrt2 缺失以剂量依赖性方式降低突触蛋白的水平，这种方式在出生后第 5 天 (P5) 最为明显，在 P60 时减弱，并在 P180 时消失。在通过平衡木时脚滑的测试中，暂时失去协调性在 P60 时最为明显，而在极端年龄时则不太明显。仅在纯合基因敲除小鼠中观察到较慢的遍历时间，这与在 Prrt2 中具有双等位基因功能突变的罕见个体中观察到的共济失调一致。因此，我们在小鼠模型中确定了三个年龄依赖性表型窗口，它们概括了人类 PRRT2 相关疾病的模式。在通过平衡木时脚滑的测试中，暂时失去协调性在 P60 时最为明显，而在极端年龄时则不太明显。仅在纯合基因敲除小鼠中观察到较慢的遍历时间，这与在 Prrt2 中具有双等位基因功能突变的罕见个体中观察到的共济失调一致。因此，我们在小鼠模型中确定了三个年龄依赖性表型窗口，它们概括了人类 PRRT2 相关疾病的模式。在通过平衡木时脚滑的测试中，暂时失去协调性在 P60 时最为明显，而在极端年龄时则不太明显。仅在纯合基因敲除小鼠中观察到较慢的遍历时间，这与在 Prrt2 中具有双等位基因功能突变的罕见个体中观察到的共济失调一致。因此，我们在小鼠模型中确定了三个年龄依赖性表型窗口，它们概括了人类 PRRT2 相关疾病的模式。