Phenotype and Functional Analyses in a Transgenic Mouse Model of Left Ventricular Noncompaction Caused by a DTNA Mutation
Phenotype and Functional Analyses in a Transgenic Mouse Model of Left Ventricular Noncompaction Caused by a DTNA Mutation
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DTNA 突变引起的左心室致密化不全转基因小鼠模型的表型和功能分析
DOI：
10.1536/ihj.16-019
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发表时间：
2017-11-01
影响因子：
1.5
通讯作者：
Hong, Kui
中科院分区：
文献类型：
--
作者：
Cao, Qing;Shen, Yang;Hong, Kui
编码dystrobrevin-α(α-DB)的DTNA是一个与左心室致密化不全心肌病(LVNC)相关的致病基因。本研究的目的是利用转基因小鼠模型研究DTNA在LVNC中的作用。通过Sanger测序，在一名LVNC患者中发现了DTNA的错义突变(c.146A和gt；G，p.N49S)。建立了6个在肌球蛋白重链6(MYH6)启动子下表达突变DTNA的转基因小鼠(MYH6：DTNA(N49S))。通过超声心动图、组织学观察和免疫印迹分析DTNA-p.N49S突变的表型特征。与对照组相比，MYH6：DTNA(N49S)组小鼠有多处心肌小梁形成，非致密心肌层与致密心肌层的比例较高。转基因小鼠还表现出左心室(LV)扩张和心脏收缩功能障碍。总之，DTNA-p.N49S突变在小鼠心脏中的过表达可能导致深部小梁、扩张性心肌病和心功能障碍的表型，这与LVNC的表型相似。
DTNA encoding dystrobrevin-alpha (alpha-DB) is a putative causal gene associated with left ventricular noncompaction cardiomyopathy (LVNC). The aim of the study was to investigate the causal role of DTNA in LVNC using a transgenic mouse model.A missense mutation (c.146A > G, p.N49S) of DTNA was identified in a patient with LVNC by Sanger sequencing. Six independent lines of transgenic mice expressing the mutant DTNA under a myosin heavy chain 6 (Myh6) promoter were generated (Myh6:Dtna(N49S)). Phenotypic characteristics of DTNA-p.N49S mutations were evaluated by echocardiography, histological observation, and immunoblotting. Multiple trabeculation and a higher ratio of non-compacted to compact myocardial layer were found in the Myh6:Dtna(N49S) mice compared to the controls. The transgenic mice also showed left ventricular (LV) dilation and cardiac systolic dysfunction. In conclusion, overexpression of the DTNA-p.N49S mutation in a mouse heart can be responsible for the phenotype of deep trabeculation, dilated cardiomyopathy, and cardiac dysfunction, which resembles the phenotype of LVNC.