Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice
Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice
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DOI：
10.1093/hmg/ddi221
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发表时间：
2005-08-01
影响因子：
3.5
通讯作者：
Stewart, CL
中科院分区：
文献类型：
--
作者：
Mounkes, LC;Kozlov, SV;Stewart, CL
核层是一层类似于10 nm厚的蛋白质层，位于内核膜之下。A-型层粘连蛋白是由LMNA基因编码的核中间丝蛋白，是核层的基本成分。LMNA的突变与椎板病、影响组织再生和内稳态的先天性疾病有关。这些与LMNA错义突变相关的椎板病变之一是扩张型心肌病伴传导系统疾病(DCM-CD1)。为了了解单个基因的不同突变是如何引起椎板病变的，我们通过同源重组获得了一个小鼠系，该品系表达了A型Lamins的Lmna-N195K变体，并在195位氨基酸上进行了天冬酰胺到赖氨酸的替代，这会导致人类DCM。该鼠系表现出与DCM-CD1一致的特征。心脏活动的连续心电监测表明，LMNA(N195K/N195K)小鼠因心律失常而早逝。通过免疫荧光和Western分析，转录因子Hf1b/SP4和缝隙连接蛋白Cx40和Cx43在Lmna(N195K/N195K)心脏中错误表达和/或错误定位。Desmin染色显示肌节和间盘组织丢失。因此，LMNA基因内的突变可能通过扰乱心肌细胞的内部组织和/或改变正常心脏发育、衰老或功能所必需的转录因子的表达而导致心肌病。
The nuclear lamina is an similar to 10 nm thick proteinaceous layer underlying the inner nuclear membrane. The A-type lamins, nuclear intermediate filament proteins encoded by the LMNA gene, are basic components of the nuclear lamina. Mutations in LMNA are associated with the laminopathies, congenital diseases affecting tissue regeneration and homeostasis. One of these laminopathies associated with missense mutations in LMNA is dilated cardiomyopathy with conduction system disease (DCM-CD1). To understand how the laminopathies arise from different mutations in a single gene, we derived a mouse line by homologous recombination expressing the Lmna-N195K variant of the A-type lamins with an asparagine-to-lysine substitution at amino acid 195, which causes DCM in humans. This mouse line shows characteristics consistent with DCM-CD1. Continuous electrocardiographic monitoring of cardiac activity demonstrated that Lmna(N195K/N195K) mice die at an early age due to arrhythmia. By immunofluorescence and western analysis, the transcription factor Hf1b/Sp4 and the gap junction proteins connexin 40 and connexin 43 were misexpressed and/or mislocalized in Lmna(N195K/N195K) hearts. Desmin staining revealed a loss of organization at sarcomeres and intercalated disks. Mutations within the LMNA gene may therefore cause cardiomyopathy by disrupting the internal organization of the cardiomyocyte and/or altering the expression of transcription factors essential to normal cardiac development, aging or function.