PDF(Pubmed)
Abstract：
Nexilin (NEXN) was recently identified as a component of the junctional membrane complex required for development and maintenance of cardiac T-tubules. Loss of Nexn in mice leads to a rapidly progressive dilated cardiomyopathy (DCM) and premature death. A 3 bp deletion (1948-1950del) leading to loss of the glycine in position 650 (G650del) is classified as a variant of uncertain significance in humans and may function as an intermediate risk allele. To determine the effect of the G650del variant on cardiac structure and function, we generated a G645del-knockin (G645del is equivalent to human G650del) mouse model. Homozygous G645del mice express about 30% of the Nexn expressed by WT controls and exhibited a progressive DCM characterized by reduced T-tubule formation, with disorganization of the transverse-axial tubular system. On the other hand, heterozygous Nexn global KO mice and genetically engineered mice encoding a truncated Nexn missing the first N-terminal actin-binding domain exhibited normal cardiac function, despite expressing only 50% and 20% of the Nexn, respectively, expressed by WT controls, suggesting that not only quantity but also quality of Nexn is necessary for a proper function. These findings demonstrated that Nexn G645 is crucial for Nexn\'s function in tubular system organization and normal cardiac function.
摘要：
Nexilin（NEXN）最近被确定为心脏T小管发育和维持所需的连接膜复合物的组成部分。小鼠中Nexn的缺失导致快速进行性扩张型心肌病(DCM)和过早死亡。导致650位甘氨酸丢失的3bp缺失（1948-1950del）（G650del）被归类为人类中具有不确定意义的变体，并且可能充当中等风险等位基因。为了确定G650del变体对心脏结构和功能的影响，我们产生了G645del-knockin(G645del相当于人类G650del)小鼠模型。纯合G645del小鼠表达WT对照表达的Nexn的约30％，并表现出进行性DCM，其特征是T管形成减少，横向轴向管状系统的解体。另一方面,杂合Nexn全局KO小鼠和编码缺失第一个N末端肌动蛋白结合域的截短Nexn的基因工程小鼠表现出正常的心脏功能，尽管只表达了50%和20%的Nexn，分别,由WT对照表示，这表明Nexn的数量和质量不仅是正确功能所必需的。这些发现表明，NexnG645对于Nexn在肾小管系统组织和正常心脏功能中的功能至关重要。
