# The role of Nexilin in cardiomyocyte and cardiomyopathy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $387,500

## Abstract

PROJECT SUMMARY
Nexilin or NEXN (encoded by NEXN) is a recently discovered Z-disc protein. NEXN is highly abundant in
cardiac muscle. Multiple mutations in NEXN have been associated with cardiomyopathies, highlighting its
importance for cardiac function. A single amino acid substitution of arginine 279 to cysteine (R279C) in NEXN
was identified as causing familial hypertrophic cardiomyopathy (HCM), and a 3-base pair (bp) deletion (1948–
1950del) leading to loss of glycine at position 650 (G650del) was found to be highly associated with dilated
cardiomyopathy (DCM). Loss of NEXN in zebrafish results in perturbed Z-disk stability and heart failure.
Interestingly, myocardial biopsies showed that NEXN mutation carriers exhibit the same cardiac Z-disk
pathology as observed in NEXN deficient and mutant zebrafish. Furthermore, global loss of NEXN in mice has
been reported to cause rapidly progressive cardiomyopathy with left ventricular dilation, wall thinning, and
decreased cardiac function, resulting in lethality shortly after birth. Premature lethality of these mice has
prevented study of the role of NEXN in adult heart function. In addition, little is known as to the specific role of
NEXN in cardiomyocytes, or mechanisms by which global loss of NEXN in mice results in rapidly progressive
cardiomyopathy. Furthermore, mechanisms by which the NEXN R279C and G650del mutations lead to the
progression of cardiomyopathy remain to be addressed. To address these questions, we have successfully
generated a floxed NEXN mouse line and will use it to generate NEXN cardiac-specific knockout (KO) mice
both during developmental and at adult stages. In addition, we have generated novel R274C (equivalent to
human R279C) and G645del (equivalent to human G650del) knock-in mouse models to characterize the role
of the human NEXN R279C and G650del mutations in cardiomyopathy. Our preliminary characterization of
global NEXN KO mice also suggests that NEXN plays an important role in regulating cardiomyocyte cell cycle
activity. The foregoing scientific premise leads us to the hypothesis that NEXN plays an essential role in
regulating cardiomyocyte cell cycle activity as well as maintaining the structural integrity of the Z-line during the
stress of muscle contraction, and that R279C and G650del mutations in NEXN impair specific aspects of
NEXN function to lead to HCM and DCM, respectively. Our Specific Aims are: 1. To characterize the role of
NEXN in the developing and adult myocardium by analyzing NEXN global and cardiomyocyte-specific
knockout mice both during development and at adult stages for cardiac function, cardiomyocyte cell cycle
activity, sarcomere integrity, and the progression of cardiomyopathy; and 2. To elucidate mechanisms
underlying cardiomyopathy consequent to R279C and G650del mutations of NEXN by analysis of R274C or
G645del mutant mice and human embryonic stem cell-derived cardiomyocytes containing NEXN R279C or
G650del mutations.

## Key facts

- **NIH application ID:** 9925817
- **Project number:** 5R01HL137957-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Ju Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2017-06-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925817

## Citation

> US National Institutes of Health, RePORTER application 9925817, The role of Nexilin in cardiomyocyte and cardiomyopathy (5R01HL137957-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9925817. Licensed CC0.

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