Identification of causative gene for Malignant Hyperthemia using exome sequencing

我们对患有恶性高热的日本家系进行了外显子组测序。该家系中携带者RYR1的所有外显子在先前的研究中都被直接测序，没有发现致病突变。为了有效地检测致病突变，我们准备了一组候选基因，其中包括1)与钙信号相关的基因，2)位于恶性高热易感区域的基因，3)在RYR1和CACNA1S高表达的组织中表达的基因，或4)直接或间接与CACNA1S或RYR1相互作用的基因。利用外显子组测序数据和候选基因集，我们鉴定了5个可能的突变。其中一个突变是编码电压门控L型钙通道阿尔法亚单位的CACNA1S。这个亚基与Ryanodine受体1相互作用。该突变是否真的是该家族的病因还有待进一步的研究，如电生理实验。

We performed exome sequencing of Japanese families with malignant hyperthermia. All exons of RYR1 of the carrier in this family were directly sequenced in previous research and no causative mutation has been found. To detect disease causing mutation efficiently, we prepared sets of candidate genes that contain 1) genes related to calcium signaling, 2) genes located on malignant hyperthermia susceptibility loci, 3) genes expressed in tissues where RYR1 and CACNA1S are highly expressed or 4) genes that interact with CACNA1S or RYR1 directly or indirectly. Using data from exome sequencing and the candidate gene sets, we identified 5 plausible mutations. One of the mutations was in CACNA1S that codes voltage-gated L-type calcium channel alpha subunit. This subunit interacts with Ryanodine receptor 1. The functional validation if this mutation is really causative of this family awaits further study such as an electrophysiological experiment.