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.
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。