Experimental Neuropediatrics, University Medical Center Hamburg-Eppendorf, Germany.
Hum Mutat. 2010 Aug;31(8):E1609-21. doi: 10.1002/humu.21302.
Cardiac sodium channels are key players in the generation and propagation of action potentials in the human heart. Heterozygous mutations in the SCN5A gene have been found to be associated with long QT syndrome, Brugada syndrome, and sinus node dysfunction (SND). Recently, overlapping arrhythmia phenotypes have been reported as well. Here we describe a novel recessive SCN5A mutation in a family originating from the German minority in White Russia. Four affected children with a history of early cardiac arrhythmia encompassing SND, conduction disease, and severe ventricular arrhythmias, are homozygous carriers of a novel SCN5A missense mutation (p.I230T) in the channel protein. Interestingly, the heterozygous mutation carriers had neither significant ECG abnormalities nor a history of cardiac events. Heterologous expression of SCN5A(I230T) channels revealed normal protein transport but altered biophysical sodium channel properties. Voltage range of both activation and inactivation were shifted in a way that resulted in decreased sodium current and loss of channel function. In conclusion, we describe a rare clinical condition with a novel SCN5A mutation causing a new type of complex cardiac arrhythmia. Unlike most previously reported sodium channelopathies, this overlap syndrome displays recessive inheritance characteristics and does not seem to follow simple Mendelian rules.
心脏钠离子通道是人类心脏动作电位产生和传播的关键因素。SCN5A 基因突变的杂合子与长 QT 综合征、Brugada 综合征和窦房结功能障碍（SND）有关。最近，也有报道称存在重叠的心律失常表型。在这里，我们描述了一个来自白俄罗斯德国少数民族的家族中的一种新型隐性 SCN5A 突变。四个受影响的孩子有早期心律失常的病史，包括 SND、传导疾病和严重的室性心律失常，他们是通道蛋白中新型 SCN5A 错义突变（p.I230T）的纯合子携带者。有趣的是，杂合子突变携带者既没有明显的心电图异常，也没有心脏事件的病史。SCN5A（I230T）通道的异源表达显示正常的蛋白转运，但改变了生物物理钠离子通道特性。激活和失活的电压范围发生了变化，导致钠离子电流减少和通道功能丧失。总之，我们描述了一种罕见的临床情况，一种新型 SCN5A 突变导致一种新型复杂的心律失常。与大多数先前报道的钠离子通道病不同，这种重叠综合征表现为隐性遗传特征，似乎不遵循简单的孟德尔法则。
