# The Role of RBM20 Sequence and Expression in Dilated Cardiomyopathies

> **NIH NIH K08** · STANFORD UNIVERSITY · 2023 · $144,994

## Abstract

PROJECT SUMMARY
 Dilated cardiomyopathy (DCM) is a deadly disease in which heterogeneous etiologies converge on
heart failure, arrhythmias, and sudden death. Although alternative RNA splicing is associated with DCM, little is
understood about specific molecular mediators of its pathogenicity. RBM20 is a cardiac muscle-specific
splicing regulator of several important cardiomyocyte genes including those critical to excitation-contraction
(EC) coupling. I have recently shown that DCM caused by genetic variants in RBM20 is particularly
arrhythmogenic, with high rates of sudden death, suggesting that RBM20’s regulation of EC coupling may
contribute to deadly arrhythmias in DCM. However, only one critical functional domain of RBM20 has been
characterized, and while its overall expression has been associated with alternative splicing in DCM, the extent
to which it directly controls splicing of key arrhythmia-associated genes in human heart failure is not known.
Therefore, I hypothesize that regional genetic variation and decreased expression of RBM20 lead to aberrant
splicing of calcium handling genes, disrupting EC coupling in human DCM.
 To address this hypothesis, I will undertake three experimental aims: First, I will determine sequence-
function relationships of variants in two regions of RBM20 highly predicted by my preliminary data to represent
functional domains. I will accomplish this using high throughput saturation gene editing of these regions in
induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) and test the functionality of resultant
genotypes by assessment of RBM20’s splicing activity. Second, to identify all RBM20-associated splicing
targets relevant to EC coupling, I will analyze global short read RNA-sequencing (RNA-seq) data from human
cardiac tissue with low vs. high RBM20 expression. I will go on to directly manipulate RBM20 expression in
iPSC-CMs and use long read RNA-seq to characterize full length isoforms of those targets under the condition
of RBM20 knockdown. Lastly, I will define the mechanism by which the aberrant splicing of two known
arrhythmia-associated RBM20 splicing targets disrupts EC coupling. To do this, I will use targeted gene editing
to correct their aberrant splice isoforms in RBM20+/- and RBM20-/- iPSC-CMs and measure the effect of this
manipulation on EC coupling-related phenotypes that I have previously established in these cell lines.
 These experiments will provide a broad basis for my future studies of global sequence-function
relationships across the length of the RBM20 transcript, as well as my future investigation of measurement and
modulation of RBM20 function to improve prognosis in DCM patients at high risk of sudden death. At the same
time, this project will develop my skills in computational biology, gene editing, and single cell electrophysiology
critical to this future investigation. Taken together, the proposed work will produce an innovative, multimodality
examination of the role of...

## Key facts

- **NIH application ID:** 10670204
- **Project number:** 5K08HL143185-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Victoria Parikh
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $144,994
- **Award type:** 5
- **Project period:** 2019-08-05 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10670204

## Citation

> US National Institutes of Health, RePORTER application 10670204, The Role of RBM20 Sequence and Expression in Dilated Cardiomyopathies (5K08HL143185-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10670204. Licensed CC0.

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