# Discovery of modifier genes in cardiomyopathy

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2021 · $629,555

## Abstract

Abstract
Cardiomyopathies (CMs) are group of inherited heterogeneous diseases of heart muscle with no definite effective
treatment, ultimately resulting in heart failure (HF), transplant or sudden cardiac death (SCD) in many patients.
Despite decades of intense research, it is still difficult to predict CM phenotypes and explain clinical heterogeneity,
severity and prognosis. The likely reason for poor genotype-phenotype association is that mutations in single
gene do not completely determine disease course; rather interactions of multiple genes, causal and modifier, may
be required to explain CM phenotypes. We have screened adult and pediatric patients with various types of CMs,
including dilated (DCM), hypertrophic (HCM) and restrictive (RCM) using whole exome sequencing (641 patients)
and direct Sanger sequencing (900 patients), and identified myopalladin (MYPN), encoding a cytoskeletal Z-disk
protein, as a strong causal gene associated with heterogeneous CM phenotypes with clinical expressions ranging
from asymptomatic left ventricular hypertrophy to dilation with progressive HF to SCD or transplant. The CM
symptoms are highly varied among individual patients, even within the same family members who carry
identical mutations. These variations are influenced by modifier genes that alter the effect of causal gene at major
locus. However, modifier genes of MYPN remain largely unidentified and are likely to depend on the interaction of
multiple genes in MYPN related gene pathways and gene networks. The identification of modifier genes is now a
crucial goal of research in CMs from the viewpoints of diagnosis, treatment and genetic counseling, but it remains
very challenging in clinical cohorts. The objective of the current study is to determine modifier genes and
molecular networks that modulate severity of MYPN induced CMs using powers of combined reverse and
forward genetics and systems genetic analysis. Systems genetics is such an approach to understand complex
diseases by focusing on how genes work together in groups rather than singly. We have confirmed that mutation
Q529X of MYPN associated with heterogeneous phenotypes in humans causes CM in knock-in mice. We have
developed the largest and best characterized mouse genetic reference population (GRP) composed of over 150
lines derived from crosses between C57BL/6J (B6) and DBA/2J (D2) parents. The D2 strain has been identified
as mouse CM model, and CM phenotypes from D2 mouse is segregated among the BXD family of strains, which
makes BXD family as an excellent platform to identify CM modifiers. Moreover, we have introduced Q526X-Mypn
mutation (homologous to human Q529X-MYPN) into BXD genetic background to examine how different genetic
background modifies the effect of Mypn mutation on CM phenotypes. This proposal is one of the first
multidisciplinary collaborative efforts to identify modifier genes in MYPN induced CM in both human and mouse.
Using cross-species validation sources and powerfu...

## Key facts

- **NIH application ID:** 10128494
- **Project number:** 5R01HL151438-02
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** LU LU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $629,555
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128494

## Citation

> US National Institutes of Health, RePORTER application 10128494, Discovery of modifier genes in cardiomyopathy (5R01HL151438-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128494. Licensed CC0.

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