# Gene x Environment Interactions and Congenital Heart Defects – Illuminating the Mechanisms

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2024 · $638,305

## Abstract

PROJECT SUMMARY
The causes of most non-syndromic structural birth defects remain unknown due to their complex causes where
genetic and environmental factors (GxE) interact to cause disease. Understanding how GxE converges to
alter embryonic development is critical for devising preventive strategies to reduce risks. Recent work by the
Zohn laboratory established a new mouse model to study the mechanisms underlying GxE interactions and
congenital heart defects (CHDs). Extensive preliminary studies with this mouse model led us to formulate our
central hypotheses: GxE converges to alter gene expression in cardiac progenitor cells to alter cell fate, and
different genetic variants in critical genes can have divergent effects on GxE interactions.
We propose two Specific Aims that use our GxE mouse models to illuminate how GxE interacts to cause
CHDs. Our experimental design involves altering the vitamin A content of the maternal diet (Environmental
factor) in mice carrying a mutation in Hectd1 (Genetic factor), a novel ubiquitin ligase discovered in the Zohn
laboratory. We show that while neither heterozygous mutation of Hectd1 nor mild vitamin A deficiency results
in CHDs, the combination of the two causes CHDs. Mechanistically we demonstrate that Hectd1 is required for
vitamin A/retinoic acid signaling, yet how HECTD1 regulates signaling remains unknown.
The aims of this project are 1) to determine how GxE converges to cause CHDs in our model and 2) to
elucidate how HECTD1 regulates retinoic acid signaling utilizing an allelic series of truncated HECTD1 mouse
lines that model human CHD-associated mutations. Interestingly, our preliminary studies indicate that distinct
mutations in HECTD1 disrupt retinoic acid signaling differently.
Successful completion of these aims will: 1) provide a deeper mechanistic understanding of how GXE interacts
to cause CHDs by elucidating which critical developmental processes are disrupted in our GxE model; 3)
reveal how HECTD1 regulates RA signaling; and 4) link our animal studies to human disorders by modeling
patient mutations in mouse models and determining how these mutations differentially interact with maternal
vitamin A intake. These studies will reveal the mechanisms of how GxE interaction alters the development of
the heart and pinpoint critical targets for preventing birth defects.

## Key facts

- **NIH application ID:** 10891723
- **Project number:** 5R01HD113214-02
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Irene E Zohn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $638,305
- **Award type:** 5
- **Project period:** 2023-07-21 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891723

## Citation

> US National Institutes of Health, RePORTER application 10891723, Gene x Environment Interactions and Congenital Heart Defects – Illuminating the Mechanisms (5R01HD113214-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10891723. Licensed CC0.

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