Why the study?
The human NEXN G650del variant is classified as a variant of uncertain significance, and its effect on cardiac structure and function was unknown.
The Nexn G645del variant causes progressive dilated cardiomyopathy in mice by disrupting T-tubule organization, demonstrating that both quantity and quality of Nexn are required for normal cardiac function.
Should not yet reclassify this NEXN VUS; leaves open G650del as an intermediate-risk allele in human DCM.
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.
No takes yet. Share an insight, caveat, or question.
Liu et al. (2020) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: