# Defining the Role of Alpha II Spectrin in Cardiac Function and Disease

> **NIH NIH F30** · OHIO STATE UNIVERSITY · 2020 · $44,205

## Abstract

PROJECT SUMMARY/ABSTRACT
 In the past fifty years, great advancements in the diagnosis, treatment and prevention of cardiovascular
disease have been made, yet cardiovascular disease remains the leading cause of death in the U.S. Notably,
over half of these deaths are associated with arrhythmias. Unfortunately, we still lack a fundamental
understanding of the molecular mechanisms underlying complex human arrhythmias. We assert that the study
of congenital arrhythmias offers significant and novel insight into pathways underlying familial and acquired
forms of cardiovascular disease. Further, combining this clinical and genetic data with targeted animal models,
electrophysiology, and molecular approaches provides exciting opportunities to identify fundamental new
information linking human disease with specific molecular mechanisms.
 Our preliminary data support a new molecular mechanism for human arrhythmia based on dysfunction
in the cardiac αII spectrin-based pathway. Specifically, our preliminary findings identify putative loss-of-
function variants in the αII spectrin pathway in patients with Brugada syndrome arrhythmias. Brugada
syndrome is a cardiac arrhythmia syndrome which causes potentially fatal ventricular arrhythmias in young
adults. It affects 1 in 2,000 adults and often presents with sudden death or syncope. The pathophysiology of
Brugada syndrome is thought to be due to the reduced action potential duration, often due to reduced sodium
outflow through the cardiac voltage gated sodium channel, Nav1.5. Spectrins are adapter molecules critical for
membrane biogenesis, organization, and signaling in neurons and erythrocytes.
 Recently, we identified two unrelated families with Brugada syndrome, each harboring a missense point
mutation in SPTAN1, which encodes αII spectrin. Notably, both variants have negligible minor allele
frequencies and are localized within three residues of each other within the C-terminal EF hand motif, an area
essential for α/β spectrin ternary complex integration with actin. However, the role of αII spectrin for cardiac
excitability is unknown and essentially unstudied, particularly for arrhythmia. Our preliminary findings in
arrhythmia patients as well as in a new animal model of cardiac αII spectrin-deficiency support new and
unexpected roles for this molecule in heart. Based on our data, we hypothesize that αII spectrin is an
unanticipated, submembrane “node” critical for ion channel and cytoskeletal regulation at the intercalated disc.
Specifically, we hypothesize that αII spectrin, through interactions with βIV spectrin, actin, and ankyrin-G,
facilitates the proper organization and function of the intercalated disc and the localization of the sodium
channel Nav1.5. Further, we predict that dysfunction in the αII spectrin pathway results in severe electrical
and structural phenotypes. We anticipate that these findings will uncover novel fundamental pathways
governing excitable cell biology.

## Key facts

- **NIH application ID:** 9967088
- **Project number:** 5F30HL137331-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Ellen Lubbers
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $44,205
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967088

## Citation

> US National Institutes of Health, RePORTER application 9967088, Defining the Role of Alpha II Spectrin in Cardiac Function and Disease (5F30HL137331-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9967088. Licensed CC0.

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