Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies
Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies
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DOI：
10.1016/j.hrthm.2008.11.009
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发表时间：
2009-03-01
期刊：
影响因子：
5.5
通讯作者：
Wilde, Arthur A. M.
中科院分区：
文献类型：
--
作者：
Meregalli, Paola G.;Tan, Hanno L.;Wilde, Arthur A. M.
背景 携带与布鲁格达综合征（BrS）或进行性心脏传导疾病（PCCD）相关的功能紊乱 SCN5A 突变的患者在年轻时面临心源性猝死的风险。该疾病的外显率和表达性变化很大，需要新的风险分层方法。 目的 我们旨在确定 SCN5A 突变类型是否与临床和心电图表型相关。 方法 我们研究了 BrS 或 PCCD 先证者及其携带 SCN5A 突变的亲属。突变分为 2 个主要组：错义突变 (M) 或导致蛋白质过早截短的突变 (T)。 M 组根据可用的生物物理特性进行细分：分别分析 90%（M-无活性）或 > 90%（M-无活性）峰值 I-Na 降低的 M 突变。 结果 研究组由 147 名具有 32 种不同突变的个体组成。各组之间没有发现年龄和性别分布差异。携带 T 突变的受试者比携带 M 活性突变的受试者发生晕厥的次数明显增多（75 人中有 19 人，35 人中有 2 人，P = 0.03）。此外，与 M 活性突变相比，与 I-Na 峰值大幅降低相关的突变（T 和 M 失活突变体）的 PR 间期明显更长。所有其他心电图参数均具有可比性。药物激发试验后，T 和 M 不活跃组的 PR 和 QRS 间期均显着长于 M 活跃组。 结论 在功能丧失的 SCN5A 通道病中，携带 T 和 M 不活跃突变的患者比携带 M 活跃突变的患者表现出更严重的表型。这与更严重的传导障碍有关。这是首次在 BrS 中提出利用遗传数据进行风险分层。
BACKGROUND Patients carrying toss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new toots for risk stratification are needed.OBJECTIVES We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype.METHODS We studied BrS or PCCD probands and their relatives who carded a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with : 90% (M-inactive) or > 90% (M-inactive) peak I-Na reduction were analyzed separately.RESULTS The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an M-active mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak I-Na reduction (T and M-inactive mutants) had a significantly longer PR interval, compared with M-active mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and M-inactive groups than in the M-active group.CONCLUSION In Loss-of-function SCN5A channelopathies, patients carrying T and M-inactive mutations develop a more severe phenotype than those with M-active mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.