Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).
Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).
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DOI：
10.1172/jci18062
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发表时间：
2003-10
期刊：
影响因子：
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通讯作者：
D. Benson;Dao-wu Wang;M. Dyment;T. Knilans;F. Fish;M. Strieper;T. H. Rhodes;A. George
中科院分区：
文献类型：
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作者：
D. Benson;Dao-wu Wang;M. Dyment;T. Knilans;F. Fish;M. Strieper;T. H. Rhodes;A. George
病窦综合征（SSS）是一种由窦房结功能障碍引起的心律失常表型，通过心电图显示窦性心动过缓或窦性停搏进行诊断。尽管经常与潜在的心脏病相关，并且最常见于老年人，但SSS可能在没有明显原因的情况下发生在胎儿、婴儿和儿童中。在这种情况下，SSS被认为是先天性的。基于先前与心脏节律和传导障碍的相关性，我们筛选了心脏钠通道（SCN 5A）的α亚基作为来自7个家庭的10名儿童患者的候选基因，这些患者在生命的第一个十年被诊断为先天性SSS。来自三个kindeles的先证者表现出六个不同的SCN 5A等位基因的复合杂合性，包括先前与心脏兴奋性显性疾病相关的两个突变。使用异源表达的重组人心脏钠通道的突变体的生物物理表征表明通道门控（失活）功能丧失或显著损伤，其预测心肌兴奋性降低。我们的研究结果揭示了某些形式的先天性SSS的分子基础，并定义了人类心脏电压门控钠通道的隐性疾病。
Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the alpha subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel.