The Role of CAV3 in Long-QT Syndrome Clinical and Functional Assessment of a Caveolin-3/Kv11.1 Double Heterozygote Versus Caveolin-3 Single Heterozygote
The Role of CAV3 in Long-QT Syndrome Clinical and Functional Assessment of a Caveolin-3/Kv11.1 Double Heterozygote Versus Caveolin-3 Single Heterozygote
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DOI：
10.1161/circgenetics.113.000137
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发表时间：
2013-10-01
影响因子：
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通讯作者：
Christiansen, Michael
中科院分区：
文献类型：
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作者：
Hedley, Paula L.;Kanters, Jorgen K.;Christiansen, Michael
背景编码caveolin-3（心脏小窝的主要支架蛋白）的CAV 3突变与骨骼肌疾病、心肌病以及最近的长QT综合征（LQTS）和婴儿猝死综合征相关。我们研究了发生在一个大的队列LQTS患者的CAV 3突变。方法和结果与LQTS先证者（n=167）进行了筛选，在CAV 3突变，使用直接DNA测序。一个先证者（0.6%）被发现是一个杂合子携带者以前描述的错义突变，小窝蛋白-3：p.T78M。先证者也是一个杂合子携带者的交通缺陷Kv11.1：p.I400N突变。在3个家族成员中发现了孤立的小窝蛋白-3：p.T78M突变，其中没有一个人有延长的QT（c）间期。在人胚肾293细胞上，采用免疫共沉淀法检测小窝蛋白3与电压门控钾通道亚基（Kv11.1）的共沉淀，并采用膜片钳技术对Kv11.1突变体进行电生理分类。此外，T波形态进行了评估，在突变携带者，双突变携带者，和非突变携带者应用形态组合评分。Caveolin-3：p.T78M携带者的形态学综合评分正常，双杂合子中的LQT 2型。此外，小窝蛋白-3：p.T78M没有表现出LQTS表型。由于尚未发现LQTS与孤立的CAV 3突变之间存在关联，因此我们建议将LQTS 9视为临时实体。
Background Mutations in CAV3, coding for caveolin-3, the major constituent scaffolding protein of cardiac caveolae, have been associated with skeletal muscle disease, cardiomyopathy, and most recently long-QT syndrome (LQTS) and sudden infant death syndrome. We examined the occurrence of CAV3 mutations in a large cohort of patients with LQTS.Methods and Results Probands with LQTS (n=167) were screened for mutations in CAV3 using direct DNA sequencing. A single proband (0.6%) was found to be a heterozygous carrier of a previously described missense mutation, caveolin-3:p.T78M. The proband was also a heterozygous carrier of the trafficking-deficient Kv11.1:p.I400N mutation. The caveolin-3:p.T78M mutation was found isolated in 3 family members, none of whom had a prolonged QT(c) interval. Coimmunoprecipitations of caveolin-3 and the voltage-gated potassium channel subunit (Kv11.1) were performed, and the electrophysiological classification of the Kv11.1 mutant was carried out by patch-clamp technique in human embryonic kidney 293 cells. Furthermore, the T-wave morphology was assessed in mutation carriers, double mutation carriers, and nonmutation carriers by applying a morphology combination score. The morphology combination score was normal for isolated caveolin-3:p.T78M carriers and of LQT2 type in double heterozygotes.Conclusions Mutations in CAV3 are rare in LQTS. Furthermore, caveolin-3:p.T78M did not exhibit a LQTS phenotype. Because no association has ever been found between LQTS and isolated CAV3 mutations, we suggest that LQTS9 is considered a provisional entity.