# Characterizing the mechanism of loss-of-function mutations in ALPK3 in the pathogenesis of cardiomyopathy

> **NIH NIH F30** · HARVARD MEDICAL SCHOOL · 2021 · $51,036

## Abstract

PROJECT ABSTRACT
 Cardiomyopathies are a broad spectrum of diseases that alter the morphology of the heart muscle. A
significant portion of previously unexplained cardiomyopathies are now understood to be the result of
mutations in genes that are highly expressed in the heart. Even for patients with other common causes of heart
failure such as hypertension or coronary artery disease, genetic variants in cardiomyopathy-associated genes
can individually or collectively affect cardiac morphology and influence disease severity. Thus, a mechanistic
understanding of the genetic causes of cardiomyopathy can reveal regulators of cardiac remodeling, a critical
first step for the development of therapeutics to attenuate these processes.
 Studies of patients with inherited forms of cardiomyopathy have revealed monogenic mutations in
genes that encode components of the sarcomere – the contractile apparatus of a cardiomyocyte. Mutations in
these sarcomeric components can impair the ability of the cardiomyocyte to contract and relax normally, and
ultimately result in pathologic remodeling and heart failure.
 Recent exome sequencing studies, conducted by our lab and others, have identified a novel
cardiomyopathy-causing gene called ALPK3. Unlike most known cardiomyopathy genes, which encode
components of the sarcomere, ALPK3 encodes a muscle-specific kinase that is localized to the nucleus.
Therefore, understanding the function of this kinase has the potential to reveal novel signals from the nucleus
that profoundly impact cardiomyocyte biology. I have created human isogenic induced pluripotent stem cell
derived cardiomyocytes (hiPSC-CMs) with and without ALPK3 mutations to interrogate the molecular pathways
in which this kinase participates, and the mechanisms by which ALPK3 mutations result in cardiomyopathy.
These studies are predicated on the hypothesis that ALPK3 mutations deplete kinase activity and/or critical
protein-protein interactions that lead to dysregulated cellular signaling and culminate in contractile dysfunction.
I will address this hypothesis with three specific aims:
Aim 1. Identify substrates of ALPK3 kinase activity and ALPK3 protein-protein interactions.
Aim 2. Characterize the effects of ALPK3 loss-of-function mutations on the cardiomyocyte
transcriptome and proteome.
Aim 3. Determine the functional effect of ALPK3 loss-of-function mutations on sarcomere dynamics.
 Collectively, these studies will provide new genetic, mechanistic, and functional insights into the role of
ALPK3 in cardiac physiology and disease.
!

## Key facts

- **NIH application ID:** 10240272
- **Project number:** 5F30HL147389-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Radhika Agarwal
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240272

## Citation

> US National Institutes of Health, RePORTER application 10240272, Characterizing the mechanism of loss-of-function mutations in ALPK3 in the pathogenesis of cardiomyopathy (5F30HL147389-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10240272. Licensed CC0.

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