# Genetic Studies of Sarcomere-based Cardiac Diseases

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $396,558

## Abstract

Dilated cardiomyopathy (DCM) is a disorder with genetic heterogeneity and variable phenotypes.
TITIN truncating variants (TTNtvs)- nonsense, frameshift, and essential splice site, has been found to be
the most common genetic factor for DCM. However, TTNtvs are also found in reference populations and it
remains unclear why pathogenic TTNtvs were mainly found in exons encoding A-band domains, while
TTNtvs in other exons such as those affecting the N-terminal Z-disc domain are likely benign. Moreover,
patients with the same TTN mutation can exhibit highly variable disease phenotypes, presumably because
of different genetic background in personal genomes. To address these two bottlenecks on TTN-based
DCM, we leveraged efficient zebrafish genetics. To fill the first knowledge gap on allelic heterogeneity, we
utilized genome-editing technology and generated more than 10 ttntvs affecting either Z-disc or A-band
exons in zebrafish. To fill the second knowledge gap on variable phenotypes, we established a novel
mutagenesis screening-based strategy and successfully identified 4 genetic modifiers for DOX-induced
cardiomyopathy. We premise that some of these modifiers and related therapies for DOX-induced
cardiomyopathy might also be applicable to TTN-based DCM. We propose to conduct comprehensive
genetic studies of these ttntvs and candidate genetic modifiers to elucidate mechanisms and to seek
therapeutic strategies for TTNtv-based DCM. In our specific Aim 1, we aim to define phenotypic traits for
ttn-based DCM, and to discern toxic peptide, exon usage and cronos hypotheses for allelic heterogeneity of
ttn-based DCM. In our specific Aim 2, we will elucidate novel functions of the short ttn-novex3 isoform, and
test the hypothesis that N-terminal ttntvs affecting the ttn-novex3 isoform are cardiomyopathy modifiers. In
our specific Aim 3, we will determine whether the 4 modifying mutants for DOX-induced cardiomyopathy
also exert similar modifying effects on ttn-based DCM, and which gene can be a therapeutic target.
Completion of the proposal will establish zebrafish as an efficient vertebrate model that facilitates the
prognosis, diagnosis and therapeutic development for cardiomyopathies including TTN-based DCM.

## Key facts

- **NIH application ID:** 9939647
- **Project number:** 5R01HL081753-14
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Xiaolei Xu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,558
- **Award type:** 5
- **Project period:** 2005-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939647

## Citation

> US National Institutes of Health, RePORTER application 9939647, Genetic Studies of Sarcomere-based Cardiac Diseases (5R01HL081753-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9939647. Licensed CC0.

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