Homozygous G650del nexilin variant causes cardiomyopathy in mice.

Canzhao Liu,Wei Feng,Xi Fang,Tongbin Wu,Kunfu Ouyang,Simone Spinozzi,Sylvia M Evans,Ju Chen,Lunfeng Zhang,Siting Zhu,Ze’E Chen

doi:10.1172/jci.insight.138780

Canzhao Liu, Wei Feng + Show 9 more

Open Access

https://doi.org/10.1172/jci.insight.138780

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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.

Highlights

Dilated cardiomyopathy (DCM) is a cardiac disorder defined by enlargement of the cardiac ventricular chambers that leads to systolic dysfunction and heart failure [1,2,3,4,5]
Gross anatomical and histological evaluation showed that NexnG645Δ/G645Δ hearts presented with average heart size, with slightly enlarged left ventricle at P10 and a progressive chamber dilation, clearly visible at 3 months of age (Figure 1F)
Mice with cardiomyocyte-specific KO of Nexn die before P12 [16], whereas a majority of NexnG645Δ/G645Δ mice are able to survive to adulthood, albeit with DCM

Summary

Introduction

Dilated cardiomyopathy (DCM) is a cardiac disorder defined by enlargement of the cardiac ventricular chambers that leads to systolic dysfunction and heart failure [1,2,3,4,5]. The study of monogenic disorders causing heart failure provides an opportunity for defining essential molecules involved in these processes and potentially creates the basis for novel tailored therapies [11,12,13]. Our previous studies have revealed that cardiomyocyte-specific ablation of Nexn results in a rapidly progressive severe DCM, identifying Nexn as a pivotal component of the junctional membrane complex (JMC) required for cardiac T-tubule development and maintenance [16]. Nexn interacts with crucial JMC proteins such as Jph, and the absence of T-tubule formation following Nexn loss in cardiomyocytes is likely due to abnormal expression of calcium-handling proteins and alterations in protein-protein interactions at the JMC [16]

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