背景:KCNQ1基因的变异,编码延迟整流器K+通道的慢分量的α-子单元,Kv7.1,导致长QT综合征1型(LQT1)。变体的位置可能是决定预后的因素之一。然而,与C端变异相关的详细基因型-表型关系仍未阐明.
目的:我们研究了携带Kv7.1C末端变异的LQTS患者的临床特征和变异特异性心律失常风险。
方法:该研究包括202名连续的LQTS患者(98名先证者和104名家庭成员),他们每个人在Kv7.1C末端携带一个罕见的杂合变体。研究其临床特征和心律失常事件。
结果:我们鉴定了36个独特的C末端变体(25个错义和11个非错义)。在8个家族中鉴定出p.R366W变体,在日本西北部的21个家庭中发现了p.T587M。至于变体的位置,我们发现,与其他区域的变异体相比,高度保守区域和非螺旋结构域的变异体与较长的QTc间期相关.p.R366W和p.T587M变体都位于高度保守和功能关键区域,靠近螺旋A和D,与钙调蛋白结合和通道组装(四聚化)有关,分别。携带p.T587M和p.R366W变体的先证者与具有其他C末端变体的先证者相比显示更差的心律失常结果。p.T587M家族的单倍型分析暗示了创始人效应。
结论:LQTS中Kv7.1的C端变异的心律失常风险是不均匀的,和变异的位置可以是预后的决定因素。
BACKGROUND: Variants in the KCNQ1 gene, encoding the α-subunit of the slow component of delayed rectifier K+ channel Kv7.1, cause long QT syndrome (LQTS) type 1. The location of variants may be one of the factors in determining prognosis. However, detailed genotype-phenotype relationships associated with C-terminus variants remain unelucidated.
OBJECTIVE: We investigated the clinical characteristics and variant-specific arrhythmic risks in patients with LQTS carrying Kv7.1 C-terminus variants.
METHODS: The study comprises 202 consecutive patients with LQTS (98 probands and 104 family members) who carry a rare heterozygous variant in the Kv7.1 C-terminus. Their clinical characteristics and arrhythmic events were investigated.
RESULTS: We identified 36 unique C-terminus variants (25 missense and 11 non-missense). The p.R366W variant was identified in 8 families, and p.T587M was identified in 21 families in large numbers from northwestern Japan. As for the location of the variant, we found that the variants in highly conserved regions and nonhelical domains were associated with longer QTc intervals compared with the variants in other regions. Both p.R366W and p.T587M variants are located in the highly conserved and functionally pivotal regions close to helices A and D, which are associated with calmodulin binding and channel assembly (tetramerization), respectively. The probands carrying p.T587M and p.R366W variants had worse arrhythmia outcomes compared with those with other C-terminus variants. The haplotype analysis of p.T587M families was suggestive of a founder effect.
CONCLUSIONS: The arrhythmic risk of C-terminus variants in Kv7.1 in LQTS is not homogeneous, and locations of variants can be a determining factor for prognosis.