Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome
Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome
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DOI：
10.1093/hmg/11.3.337
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发表时间：
2002-02-01
影响因子：
3.5
通讯作者：
Towbin, JA
中科院分区：
文献类型：
--
作者：
Vatta, M;Dumaine, R;Towbin, JA
不明原因夜间猝死综合征（SUNDS）是一种在东南亚发现的疾病，其特征是心电图异常，V1-V3导联ST段抬高，心室颤动导致猝死，与Brugada综合征相同。我们对SUNDS患者进行了SCN 5A突变的筛查，SCN 5A是已知引起Brugada综合征的基因，以及编码与长QT综合征相关的离子通道的基因。入选10个家系，采用单链DNA构象多态性分析、变性高效液相色谱和DNA测序进行突变筛查。在3个家系中发现了SCN 5A突变。一个突变R367 H位于SCN 5A的DIS 5和DIS 6跨膜区段之间的孔衬区的第一个P区段。第二个突变A735 V位于结构域II（DIIS 1）的第一个跨膜段，靠近DIIS 1和DIIS 2之间的第一个细胞外环，而第三个突变R1192 Q位于结构域III。对异种卵母细胞中这些突变的分析表明，R367 H突变通道不表达任何电流，并且该突变的可能作用是由于一个功能等位基因的丢失而降低峰值电流。A735 V突变体表达电流，稳态激活电压向更正的电位移动。R1192 Q突变加速了钠通道电流的失活。两种突变均导致钠通道电流（I-Na）在对应于动作电位1相结束的时间降低，如先前在Brugada综合征中所述。基于这些观察，我们认为，SUNDS和Brugada综合征是表型，遗传和功能相同的疾病。
Sudden unexplained nocturnal death syndrome (SUNDS), a disorder found in southeast Asia, is characterized by an abnormal electrocardiogram with ST-segment elevation in leads V1-V3 and sudden death due to ventricular fibrillation, identical to that seen in Brugada syndrome. We screened patients with SUNDS for mutations in SCN5A, the gene known to cause Brugada syndrome, as well as genes encoding ion channels associated with the long-QT syndrome. Ten families were enrolled, and screened for mutations using single-strand DNA conformation polymorphism analysis, denaturing high-performance liquid chromatography and DNA sequencing. Mutations were identified in SCN5Ain three families. One mutation, R367H, lies in the first P segment of the pore-lining region between the DIS5 and DIS6 transmembrane segments of SCN5A. A second mutation, A735V, lies in the first transmembrane segment of domain II (DIIS1) close to the first extracellular loop between DIIS1 and DIIS2, whereas the third mutation, R1192Q, lies in domain III. Analysis of these mutations in Xenopusoocytes showed that the R367H mutant channel did not express any current and the likely effect of this mutation is to depress peak current due to the loss of one functional allele. The A735V mutant expressed currents with steady state activation voltage shifted to more positive potentials. The R1192Q mutation accelerated the inactivation of the sodium channel current. Both mutations resulted in reduced sodium channel current (I-Na) at a time corresponding to the end of phase 1 of the action potential, as described previously in the Brugada syndrome. Based upon these observations we suggest that SUNDS and Brugada syndrome are phenotypically, genetically and functionally the same disorder.