# Understanding the roles of nuclear envelope proteins and DNA damage in cardiomyopathy

> **NIH NIH K99** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $100,480

## Abstract

Project Summary
Mutations in nuclear envelope proteins (NEPs) cause devastating genetic diseases, known as
envelopathies, which primarily affect the heart and skeletal muscle. The LEM domain nuclear envelope
protein 2 (LEMD2) is a ubiquitously expressed inner nuclear membrane protein. In vitro studies reported
that LEMD2 interacts with DNA-binding proteins, implicating LEMD2 in genome regulation and
chromatin organization processes. Importantly, a missense mutation in the LEMD2 coding sequence
causes severe cardiomyopathy in humans. In a recent study, we reported that “humanized” mice
carrying the Lemd2 c.T38>G human mutation as well as cardiac-specific Lemd2 KO (cKO) mice
develop dilated cardiomyopathy (DCM) and die prematurely due to heart failure. Moreover, Lemd2-
deficient cardiomyocytes (CMs) display high levels of DNA damage. Despite its association with cardiac
phenotypes in both human and mice, the role of LEMD2 in the mammalian heart and the pathological
mechanisms responsible for its association with cardiac disease are far from being understood.
Based on my preliminary findings, I hypothesize that high levels of DNA damage in LEMD2-mutant
CMs cause the development of cardiomyopathy. To test this hypothesis, I will first perform a
comprehensive characterization of the DNA damage and DNA damage response (DDR) in both mice
and human CMs carrying LEMD2 mutations. The second aim is focused on the mechanistic link
between LEMD2 loss-of-function, DNA damage and cardiomyopathy. I will determine if LEMD2
interacts with the chromatin-binding protein BAF, and whether the LEMD2 c.T38>G mutation disrupts
this interaction. I will also detect nuclear envelope ruptures, cytosolic DNA leakage, and the activation
of the pro-inflammatory pathway cGAS in LEMD2-mutant CMs. The third aim will determine the
therapeutic potential of LEMD2 gene therapy for envelopathies characterized by the presence of DNA
damage. I will overexpress LEMD2 in CMs and mice carrying mutations in the lamin A gene and assess
the extent of rescue at the structural and functional levels.
By accomplishing the objectives of this proposal, we will reveal important mechanistic insights
regarding LEMD2 functions and its associated cardiomyopathy. With this new knowledge, we hope to
ultimately design new therapeutic strategies and preventive methods for genetic cardiomyopathies.

## Key facts

- **NIH application ID:** 10984733
- **Project number:** 1K99HL171887-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Xurde Menendez Caravia
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $100,480
- **Award type:** 1
- **Project period:** 2024-08-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984733

## Citation

> US National Institutes of Health, RePORTER application 10984733, Understanding the roles of nuclear envelope proteins and DNA damage in cardiomyopathy (1K99HL171887-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10984733. Licensed CC0.

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