Imai Michiko, Nakajima Tadashi, Kaneko Yoshiaki, Niwamae Nogiku, Irie Tadanobu, Ota Masaki, Iijima Takafumi, Tange Shoichi, Kurabayashi Masahiko
Department of Cardiovascular Medicine, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan.
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
J Cardiol. 2014 Aug;64(2):121-6. doi: 10.1016/j.jjcc.2013.11.014. Epub 2013 Dec 25.
Several KCNQ1 splicing mutations have been identified in patients with type-1 long QT syndrome (LQT1). It was suggested that the clinical severity may differ according to the aberrant splicing products. There may be precipitating factors that cause cardiac events in those with a mild clinical phenotype (forme fruste LQT1).
We analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 31 consecutive LQTS patients. A novel KCNQ1 1251+1G>A (IVS9+1G>A) mutation was identified in three probands and their two relatives. The QT interval in all of the five individuals with mutation was not much prolonged in the absence of precipitating factors (mean QTc was 461±30ms.). Two of the five individuals with mutation were symptomatic. One patient (a 38-year-old female) had experienced recurrent episodes of syncope due to ventricular tachyarrhythmias (VTAs) accompanied by QT prolongation (QTc: 750ms) when the serum potassium concentration ([K(+)]) was 2.7mEq/L. After correction of [K(+)], the QTc interval was shortened to 515ms, and the occurrence of VTAs ceased. Another patient (a 22-year-old female) was resuscitated from cardio-pulmonary arrest due to VTAs. Just after resuscitation, the QTc interval was 629ms, and [K(+)] was 2.9mEq/L. After correction of [K(+)], the QTc interval was dramatically shortened to 440ms. In order to identify abnormal splicing products of the responsible mutation, we analyzed the reverse transcription-polymerase chain reaction products from peripheral bloods of the mutation carrier, and identified exon 9-skipping (Δ9) and cryptic sequential exons 8 and 9-skipping (Δ8-9) products, as well as a no exon-skipping product.
We identified a novel KCNQ splicing mutation 1251+1G>A in forme fruste LQT1, which induces cryptic splicing. Two of the five individuals with mutation experienced VTAs in the setting of hypokalemia, emphasizing the need to increase awareness of the significance of hypokalemia in this subgroup of LQT1 patients.
在1型长QT综合征（LQT1）患者中已鉴定出几种KCNQ1剪接突变。有人提出，临床严重程度可能因异常剪接产物而异。在临床表型较轻的患者（顿挫型LQT1）中可能存在引发心脏事件的诱发因素。
我们分析了31例连续性LQTS患者的KCNQ1、KCNH2、SCN5A、KCNE1和KCNE2基因。在三名先证者及其两名亲属中鉴定出一种新的KCNQ1 1251+1G>A（IVS9+1G>A）突变。在没有诱发因素的情况下，所有五名携带突变的个体的QT间期延长不多（平均QTc为461±30ms）。五名携带突变的个体中有两名有症状。一名患者（38岁女性）在血清钾浓度（[K(+)]）为2.7mEq/L时，因室性快速心律失常（VTA）伴QT延长（QTc：750ms）而反复出现晕厥。纠正[K(+)]后，QTc间期缩短至515ms，VTA发作停止。另一名患者（22岁女性）因VTA导致心肺骤停后复苏成功。复苏后即刻，QTc间期为629ms，[K(+)]为2.9mEq/L。纠正[K(+)]后，QTc间期显著缩短至440ms。为了鉴定相关突变的异常剪接产物，我们分析了突变携带者外周血的逆转录-聚合酶链反应产物，鉴定出外显子9跳跃（Δ9）、隐匿性连续外显子8和9跳跃（Δ8-9）产物以及无外显子跳跃产物。
我们在顿挫型LQT1中鉴定出一种新的KCNQ剪接突变1251+1G>A，其诱导隐匿性剪接。五名携带突变的个体中有两名在低钾血症情况下发生VTA，强调需要提高对低钾血症在该LQT1患者亚组中的重要性的认识。
