# Defining Novel Mechanisms underlying Human Arrhythmogenic Cardiomyopathy

> **NIH NIH F30** · OHIO STATE UNIVERSITY · 2020 · $35,785

## Abstract

Project Summary/Abstract
Defining Novel Mechanisms underlying Human Arrhythmogenic Cardiomyopathy
Arrhythmogenic cardiomyopathy (AC, also termed ARVC) is a complex and potentially fatal disease commonly
associated with ventricular arrhythmias in young adults. AC is an inherited disorder primarily associated with
loss-of-function gene variants in cardiac desmosomal proteins. However, as the full spectrum of AC disease
genes is still unknown, we unfortunately lack critical information essential for the diagnosis and treatment of
this devastating disease. We seek to identify a new genetic/molecular mechanism for human AC. Our data
that include clinical, pathological, genetic, in vivo, biochemical, and molecular studies support a new and
unexpected molecular mechanism underlying human AC. Specifically, we have identified ANK2 (encodes
AnkB) as a human AC candidate gene. Notably, unlike most AC disease genes, AnkB is not a desmosomal
protein. Patients harboring ANK2 loss-of-function variants display AC resulting in sudden cardiac death. A new
mouse model of cardiac-restricted AnkB deletion phenocopies human AC displaying structural remodeling,
fibrosis, and early mortality. Finally, our data support an unanticipated mechanism for cardiac AnkB.
Specifically, our data support that: 1) AnkB directly binds β-catenin, a molecule tightly linked with cardiac Wnt
signaling in AC, and 2) β-catenin regulation is altered in hearts of human ANK2 AC and AnkB cKO hearts. Our
objective is to define the molecular mechanisms underlying AnkB dysfunction in human AC. Our preliminary
data support a conclusion that AnkB is critical for cardiac structural and electrical function, and plays an
unexpected role in β-catenin regulation. Further, our data supports that AnkB dysfunction in humans and mice
results in maladaptive remodeling, heart failure, arrhythmia, and ultimately early death associated with altered
β-catenin activity.

## Key facts

- **NIH application ID:** 10005450
- **Project number:** 5F30HL137325-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Nathaniel Patrick Murphy
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $35,785
- **Award type:** 5
- **Project period:** 2017-09-01 → 2021-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005450

## Citation

> US National Institutes of Health, RePORTER application 10005450, Defining Novel Mechanisms underlying Human Arrhythmogenic Cardiomyopathy (5F30HL137325-04). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10005450. Licensed CC0.

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