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Abstract：
KCNMA1 forms the pore of BK K+ channels, which regulate neuronal and muscle excitability. Recently, genetic screening identified heterozygous KCNMA1 variants in a subset of patients with debilitating paroxysmal non-kinesigenic dyskinesia, presenting with or without epilepsy (PNKD3). However, the relevance of KCNMA1 mutations and the basis for clinical heterogeneity in PNKD3 has not been established. Here, we evaluate the relative severity of three KCNMA1 patient variants in BK channels, neurons, and mice. In heterologous cells, BKN999S and BKD434G channels displayed gain-of-function (GOF) properties, whereas BKH444Q channels showed loss-of-function (LOF) properties. The relative degree of channel activity was BKN999S > BKD434G>WT > BKH444Q. BK currents and action potential firing were increased, and seizure thresholds decreased, in Kcnma1N999S/WT and Kcnma1D434G/WT transgenic mice but not Kcnma1H444Q/WT mice. In a novel behavioral test for paroxysmal dyskinesia, the more severely affected Kcnma1N999S/WT mice became immobile after stress. This was abrogated by acute dextroamphetamine treatment, consistent with PNKD3-affected individuals. Homozygous Kcnma1D434G/D434G mice showed similar immobility, but in contrast, homozygous Kcnma1H444Q/H444Q mice displayed hyperkinetic behavior. These data establish the relative pathogenic potential of patient alleles as N999S>D434G>H444Q and validate Kcnma1N999S/WT mice as a model for PNKD3 with increased seizure propensity.
So far, only 70 patients around the world have been diagnosed with a newly identified rare syndrome known as KCNMA1-linked channelopathy. The condition is characterised by seizures and abnormal movements which include frequent ‘drop attacks’, a sudden and debilitating loss of muscle control that causes patients to fall without warning. The disease is associated with mutations in the gene for KCNMA1, a member of a class of proteins important for controlling nerve cell activity and brain function. However, due to the limited number of people affected by the condition, it is difficult to link a particular mutation to the observed symptoms; the basis for the drop attacks therefore remains unknown. Park et al. set out to ‘model’ KCNMA1-linked channelopathy in the laboratory, in order to determine which mutations in the KCNMA1 gene caused these symptoms. Three groups of mice were each genetically engineered to carry either one of the two most common mutations in the gene for KCNMA1, or a very rare mutation associated with the movement symptoms. Behavioural experiments and studies of nerve cell activity revealed that the mice carrying mutations that made the KCNMA1 protein more active developed seizures more easily and became immobilized, showing the mouse version of drop attacks. Giving these mice the drug dextroamphetamine, which works in some human patients, stopped the immobilizing attacks altogether. These results show for the first time which specific genetic changes cause the main symptoms of KCNMA1-linked channelopathy. Park et al. hope that this knowledge will deepen our understanding of this disease and help develop better treatments.
So far, only 70 patients around the world have been diagnosed with a newly identified rare syndrome known as KCNMA1-linked channelopathy. The condition is characterised by seizures and abnormal movements which include frequent ‘drop attacks’, a sudden and debilitating loss of muscle control that causes patients to fall without warning. The disease is associated with mutations in the gene for KCNMA1, a member of a class of proteins important for controlling nerve cell activity and brain function. However, due to the limited number of people affected by the condition, it is difficult to link a particular mutation to the observed symptoms; the basis for the drop attacks therefore remains unknown. Park et al. set out to ‘model’ KCNMA1-linked channelopathy in the laboratory, in order to determine which mutations in the KCNMA1 gene caused these symptoms. Three groups of mice were each genetically engineered to carry either one of the two most common mutations in the gene for KCNMA1, or a very rare mutation associated with the movement symptoms. Behavioural experiments and studies of nerve cell activity revealed that the mice carrying mutations that made the KCNMA1 protein more active developed seizures more easily and became immobilized, showing the mouse version of drop attacks. Giving these mice the drug dextroamphetamine, which works in some human patients, stopped the immobilizing attacks altogether. These results show for the first time which specific genetic changes cause the main symptoms of KCNMA1-linked channelopathy. Park et al. hope that this knowledge will deepen our understanding of this disease and help develop better treatments.
摘要：
KCNMA1形成BK+通道的孔隙,调节神经元和肌肉的兴奋性。最近,遗传筛查在一组衰弱性阵发性非运动源性运动障碍患者中鉴定出杂合的KCNMA1变体，有或没有癫痫（PNKD3）。然而,KCNMA1突变的相关性和PNKD3临床异质性的基础尚未确定.这里,我们评估了BK通道中三种KCNMA1患者变异的相对严重程度，神经元，和老鼠。在异源细胞中，BKN999S和BKD434G通道显示功能增益(GOF)属性，而BKH444Q通道显示功能丧失(LOF)特性。通道活性的相对程度为BKN999S>BKD434G>WT>BKH444Q。BK电流和动作电位放电增加，癫痫发作阈值降低，在Kcnma1N999S/WT和Kcnma1D434G/WT转基因小鼠中，但不在Kcnma1H444Q/WT小鼠中。在一项新的阵发性运动障碍行为测试中，受影响更严重的Kcnma1N999S/WT小鼠在应激后变得不动。急性右旋苯丙胺治疗消除了这种情况，与受PNKD3影响的个体一致。纯合子Kcnma1D434G/D434G小鼠表现出相似的不动，但相比之下,纯合Kcnma1H444Q/H444Q小鼠表现出运动过度行为。这些数据建立了患者等位基因的相对致病潜力为N999S>D434G>H444Q,并验证了Kcnma1N999S/WT小鼠作为癫痫发作倾向增加的PNKD3模型。
到目前为止,全球仅有70例患者被诊断出患有一种新发现的罕见综合征,即KCNMA1相关信道病.这种情况的特征是癫痫发作和异常运动，包括频繁的“跌落攻击”，肌肉控制的突然和衰弱的丧失，导致患者在没有警告的情况下跌倒。该疾病与KCNMA1基因的突变有关，KCNMA1是一类对控制神经细胞活性和脑功能重要的蛋白质的成员。然而,由于受影响的人数有限，很难将特定的突变与观察到的症状联系起来;因此，下降攻击的基础仍然未知。Park等人。在实验室中开始“模型”KCNMA1链接的信道作用，为了确定KCNMA1基因中的哪些突变引起了这些症状。三组小鼠均经过基因工程改造，以携带KCNMA1基因中两个最常见的突变之一，或与运动症状相关的非常罕见的突变。行为实验和神经细胞活性的研究表明，携带突变使KCNMA1蛋白更活跃的小鼠更容易发生癫痫发作，并被固定，显示鼠标版本的drop攻击。给这些老鼠服用右旋苯丙胺，对一些人类患者有效，完全停止了固定的攻击。这些结果首次显示了哪些特定的遗传变化引起了KCNMA1连锁信道病的主要症状。Park等人。希望这些知识将加深我们对这种疾病的理解，并帮助开发更好的治疗方法。
到目前为止,全球仅有70例患者被诊断出患有一种新发现的罕见综合征,即KCNMA1相关信道病.这种情况的特征是癫痫发作和异常运动，包括频繁的“跌落攻击”，肌肉控制的突然和衰弱的丧失，导致患者在没有警告的情况下跌倒。该疾病与KCNMA1基因的突变有关，KCNMA1是一类对控制神经细胞活性和脑功能重要的蛋白质的成员。然而,由于受影响的人数有限，很难将特定的突变与观察到的症状联系起来;因此，下降攻击的基础仍然未知。Park等人。在实验室中开始“模型”KCNMA1链接的信道作用，为了确定KCNMA1基因中的哪些突变引起了这些症状。三组小鼠均经过基因工程改造，以携带KCNMA1基因中两个最常见的突变之一，或与运动症状相关的非常罕见的突变。行为实验和神经细胞活性的研究表明，携带突变使KCNMA1蛋白更活跃的小鼠更容易发生癫痫发作，并被固定，显示鼠标版本的drop攻击。给这些老鼠服用右旋苯丙胺，对一些人类患者有效，完全停止了固定的攻击。这些结果首次显示了哪些特定的遗传变化引起了KCNMA1连锁信道病的主要症状。Park等人。希望这些知识将加深我们对这种疾病的理解，并帮助开发更好的治疗方法。
