Variable Na(v)1.5 protein expression from the wild-type allele correlates with the penetrance of cardiac conduction disease in the Scn5a(+/-) mouse model.
Variable Na(v)1.5 protein expression from the wild-type allele correlates with the penetrance of cardiac conduction disease in the Scn5a(+/-) mouse model.
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DOI：
10.1371/journal.pone.0009298
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发表时间：
2010-02-19
期刊：
影响因子：
3.7
通讯作者：
Charpentier F
中科院分区：
文献类型：
--
作者：
Leoni AL;Gavillet B;Rougier JS;Marionneau C;Probst V;Le Scouarnec S;Schott JJ;Demolombe S;Bruneval P;Huang CL;Colledge WH;Grace AA;Le Marec H;Wilde AA;Mohler PJ;Escande D;Abriel H;Charpentier F
SCN 5A（编码Nav1.5 Na+通道的基因）的功能缺失突变与遗传性心脏传导缺陷和Brugada综合征相关，这两种疾病都表现出不同的传导缺陷表型突变率。我们在Scn 5a杂合靶向破坏的小鼠模型（Scn 5a +/−小鼠）中研究了这种异质性的机制，并将我们的结果与SCN 5A功能缺失突变患者的结果进行了比较。根据心电图，将10周龄Scn 5a +/−小鼠分为2个亚组，一个亚组显示重度心室传导缺陷（QRS间期>18 ms），另一个亚组显示轻度表型（QRS≤18 ms;野生型同窝仔中的QRS：10-18 ms）。表型差异持续与老化。在10周时，Na+通道阻滞剂ajurone延长了两组Scn 5a +/−小鼠的QRS间期。相比之下，在老年小鼠（>53周）中，严重受累亚组中的阿曲库铵效应更大。这些数据与对患有SCN 5A功能丧失突变的患者的临床观察结果相匹配，这些患者患有严重或轻度传导缺陷。5/10只严重受累的Scn 5a +/−小鼠出现室性心动过速，但轻度受累小鼠未出现室性心动过速。相应地，有症状的SCN 5A突变的Brugada患者比无症状患者有更严重的传导缺陷。老年严重受累的Scn 5a +/−小鼠（而非轻度受累小鼠）表现出广泛的心脏纤维化。与严重受累的Scn 5a +/−小鼠相比，轻度受累的Scn 5a +/−小鼠具有相似的Nav1.5 mRNA，但较高的Nav1.5蛋白表达，以及中等程度较大的INa电流。因此，严重受影响的Scn 5a +/−小鼠的动作电位上行速度比轻度受影响的小鼠下降得更多。 Scn 5a +/−小鼠表现出与SCN 5A突变患者相似的表型异质性。在Scn 5a +/−小鼠中，表型严重程度与野生型Nav1.5蛋白表达相关。
Loss-of-function mutations in SCN5A, the gene encoding Nav1.5 Na+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a +/− mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A. Based on ECG, 10-week-old Scn5a +/− mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS≤18 ms; QRS in wild-type littermates: 10–18 ms). Phenotypic difference persisted with aging. At 10 weeks, the Na+ channel blocker ajmaline prolonged QRS interval similarly in both groups of Scn5a +/− mice. In contrast, in old mice (>53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a +/− mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A–mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a +/− mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a +/− mice had similar Nav1.5 mRNA but higher Nav1.5 protein expression, and moderately larger INa current than severely affected Scn5a +/− mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a +/− mice than in mildly affected ones. Scn5a +/− mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a +/− mice, phenotype severity correlates with wild-type Nav1.5 protein expression.
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DOI：
10.1073/pnas.0403711101
发表时间：
2004-12-14
影响因子：
11.1
作者：
Mohler, PJ;Rivolta, I;Bennett, V
通讯作者：
Bennett, V
影响因子：
5.5
作者：
Balasubramaniam, R;Grace, AA;Huang, CLH
通讯作者：
Huang, CLH
影响因子：
5.5
作者：
Marionneau, C;Couette, B;Demolombe, S
通讯作者：
Demolombe, S
DOI：
10.1111/j.1540-8167.2007.01050.x
发表时间：
2008-04-01
影响因子：
2.7
作者：
Junttila, M. Juhani;Brugada, Pedro;Brugada, Ramon
通讯作者：
Brugada, Ramon
DOI：
10.1152/ajpheart.01060.2005
发表时间：
2006-06-01
影响因子：
4.8
作者：
Boixel, Christophe;Gavillet, Bruno;Abriel, Hugues
通讯作者：
Abriel, Hugues