Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland.
Int J Cardiol. 2011 Mar 3;147(2):246-52. doi: 10.1016/j.ijcard.2009.08.041. Epub 2009 Sep 25.
Catecholaminergic polymorphic ventricular tachycardia caused by mutations in the RyR2 gene manifests as severe arrhythmias, and may provide a candidate for sudden cardiac deaths.
We screened 19 victims of SCD for mutations in the RyR2 gene by direct sequencing, and analyzed DNAs from available family members and from 300 controls. Medico-legal investigations were conducted by experienced pathologists. We performed resting ECG, cardiac ultrasonography, exercise stress test, epinephrine test and 24-hour ambulatory ECG recording to related mutation carriers (n = 17). The single channel recordings of the mutant RyR2s were conducted in planar lipid bilayers, and the open probabilities were determined by sequential addition of CaCl(2) to the cis-side.
We identified two novel RyR2 missense mutations (G2145R and R3570W) in three victims of SCD. The surviving carriers of these mutations exhibited only minor, if any structural abnormalities, and two carriers of R3570W showed ventricular arrhythmias predominantly at rest. Single channel recordings revealed a gain-of-function defect in native unphosphorylated R3570W and a similar but milder defect in native G2145R.
RyR2 mutations manifesting as a gain-of-function defect in vitro may be detectable in some cases of SCD. Not all RyR2 mutations lead to a uniform, highly penetrant CPVT phenotype.
编码 RyR2 基因的突变可引起儿茶酚胺多形性室性心动过速，表现为严重的心律失常，可能成为心源性猝死的候选因素。
我们通过直接测序对 19 例 SCD 患者的 RyR2 基因突变进行了筛选，并对可获得的家族成员和 300 名对照者的 DNA 进行了分析。医学法律调查由经验丰富的病理学家进行。我们对相关突变携带者（n = 17）进行了静息心电图、心脏超声、运动应激试验、肾上腺素试验和 24 小时动态心电图记录。在平面脂质双层中对突变 RyR2 进行了单通道记录，并通过向 cis 侧连续添加 CaCl2 来确定开放概率。
我们在 3 例 SCD 患者中发现了两个新的 RyR2 错义突变（G2145R 和 R3570W）。这些突变的幸存者携带者仅表现出轻微的结构异常，如果有的话，并且两个 R3570W 携带者主要在休息时出现室性心律失常。单通道记录显示，天然非磷酸化 R3570W 存在功能获得性缺陷，而天然 G2145R 存在类似但较轻微的缺陷。
体外表现为功能获得性缺陷的 RyR2 突变可能在某些 SCD 病例中可检测到。并非所有 RyR2 突变都会导致一致的、高外显率的 CPVT 表型。
