Medeiros-Domingo Argelia, Tan Bi-Hua, Iturralde-Torres Pedro, Tester David J, Tusié-Luna Teresa, Makielski Jonathan C, Ackerman Michael J
Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA.
Heart Rhythm. 2009 Aug;6(8):1170-5. doi: 10.1016/j.hrthm.2009.04.034. Epub 2009 May 4.
Functional characterization of mutations involving the SCN5A-encoded cardiac sodium channel has established the pathogenic mechanisms for type 3 long QT syndrome and type 1 Brugada syndrome and has provided key insights into the physiological importance of essential structure-function domains.
This study sought to present the clinical and biophysical phenotypes discerned from compound heterozygosity mutations in SCN5A on different alleles in a toddler diagnosed with QT prolongation and fever-induced ventricular arrhythmias.
A 22-month-old boy presented emergently with fever and refractory ventricular tachycardia. Despite restoration of sinus rhythm, the infant sustained profound neurological injury and died. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, comprehensive open-reading frame/splice mutational analysis of the 12 known long QT syndrome susceptibility genes was performed.
The infant had 2 SCN5A mutations: a maternally inherited N-terminal frame shift/deletion (R34fs/60) and a paternally inherited missense mutation, R1195H. The mutations were engineered by site-directed mutagenesis and heterologously expressed transiently in HEK293 cells. As expected, the frame-shifted and prematurely truncated peptide, SCN5A-R34fs/60, showed no current. SCN5A-R1195H had normal peak and late current but abnormal voltage-dependent gating parameters. Surprisingly, co-expression of SCN5A-R34fs/60 with SCN5A-R1195H elicited a significant increase in late sodium current, whereas co-expression of SCN5A-WT with SCN5A-R34fs/60 did not.
A severe clinical phenotype characterized by fever-induced monomorphic ventricular tachycardia and QT interval prolongation emerged in a toddler with compound heterozygosity involving SCN5A: R34fs/60, and R1195H. Unexpectedly, the 94-amino-acid fusion peptide derived from the R34fs/60 mutation accentuated the late sodium current of R1195H-containing Na(V)1.5 channels in vitro.
涉及由SCN5A编码的心脏钠通道的突变的功能特性已确立了3型长QT综合征和1型Brugada综合征的致病机制，并为基本结构-功能域的生理重要性提供了关键见解。
本研究旨在呈现从一名被诊断为QT延长和发热诱导的室性心律失常的幼儿中不同等位基因上SCN5A复合杂合突变所识别出的临床和生物物理表型。
一名22个月大的男孩因发热和难治性室性心动过速紧急就诊。尽管恢复了窦性心律，但该婴儿仍遭受了严重的神经损伤并死亡。使用聚合酶链反应、变性高效液相色谱和直接DNA测序，对12个已知的长QT综合征易感基因进行了全面的开放阅读框/剪接突变分析。
该婴儿有2个SCN5A突变：一个母系遗传的N端移码/缺失（R34fs/60）和一个父系遗传的错义突变R1195H。通过定点诱变构建突变体，并在HEK293细胞中瞬时异源表达。正如预期的那样，移码且过早截断的肽SCN5A-R34fs/60没有电流。SCN5A-R1195H具有正常的峰值和晚期电流，但电压依赖性门控参数异常。令人惊讶的是，SCN5A-R34fs/60与SCN5A-R1195H共表达会引起晚期钠电流显著增加，而SCN5A-WT与SCN5A-R34fs/60共表达则不会。
一名患有涉及SCN5A：R34fs/60和R1195H的复合杂合性的幼儿出现了以发热诱导的单形性室性心动过速和QT间期延长为特征的严重临床表型。出乎意料的是, 源自R34fs/60突变的94个氨基酸的融合肽在体外增强了含R119５H的Na(V)1.5通道 的晚期钠电流。
