Targeted point mutagenesis of mouse Kcnq1:: phenotypic analysis of mice with point mutations that cause Romano-Ward syndrome in humans
Targeted point mutagenesis of mouse Kcnq1:: phenotypic analysis of mice with point mutations that cause Romano-Ward syndrome in humans
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DOI：
10.1016/j.ygeno.2004.06.007
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发表时间：
2004-09-01
期刊：
影响因子：
4.4
通讯作者：
Pfeifer, K
中科院分区：
文献类型：
--
作者：
Casimiro, MC;Knollmann, BC;Pfeifer, K
遗传性长QT综合征最常与KCNQ 1突变相关，KCNQ 1编码钾通道的初级亚基。KCNQ 1突变的患者可能仅表现出心脏缺陷（Romano-Ward综合征或RWS），也可能患有严重耳聋（Jervell和Lange-Nielsen综合征或JLNS）。小鼠Kcnq 1模型JLNS的靶向破坏，因为小鼠耳聋并显示异常ECG。然而，表型比在患者中观察到的表型更广泛。最引人注目的是，内耳缺陷导致严重的多动症/盘旋行为，这可能影响心脏功能。为了了解这些小鼠心脏表型的病因并产生潜在的更有用的模型系统，我们通过引入与RWS相关的点突变产生了新的小鼠品系。A340 E系表型模仿RWS：复极表型以显性方式遗传，并且观察到与任何内耳缺陷无关。T3 III系表型模仿JLNS，耳聋与内毛细胞功能障碍有关。(C)2004年爱思唯尔公司All rights reserved.
Inherited long QT syndrome is most frequently associated with mutations in KCNQ1, which encodes the primary subunit of a potassium channel. Patients with mutations in KCNQ1 may show only the cardiac defect (Romano-Ward syndrome or RWS) or may also have severe deafness (Jervell and Lange-Nielsen syndrome or JLNS). Targeted disruption of mouse Kcnq1 models JLNS in that mice are deaf and show abnormal ECGs. However, the phenotype is broader than that seen in patients. Most dramatically, the inner ear defects result in a severe hyperactivity/circling behavior, which may influence cardiac function. To understand the etiology of the cardiac phenotype in these mice and to generate a potentially more useful model system, we generated new mouse lines by introducing point mutations associated with RWS. The A340E line phenocopies RWS: the repolarization phenotype is inherited in a dominant manner and is observed independent of any inner ear defect. The T3III line phenocopies JLNS, with deafness associated with inner hair cell malfunction. (C) 2004 Elsevier Inc. All rights reserved.