# Understanding the role of PRDM1 in limb development and split hand/foot malformation.

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2020 · $36,720

## Abstract

PROJECT SUMMARY/ABSTRACT
 Limb development is strictly regulated by gene regulatory networks governed by a complex network of
regulatory elements, transcription factors, and epigenetic modifiers. Each component is interconnected, and
misregulation at any point in the developmental timeline can lead to congenital limb defects, which affect 1 in
2,000 newborns. One factor that regulates early limb initiation and outgrowth in both mice and zebrafish is
PRDM1, though the mechanism is unknown. Uncovering this has become increasingly more important as we
have recently identified three human families with split hand/foot malformation (SHFM) of unknown genetic
etiology but potentially pathogenic PRDM1 variants. PRDM1 is a versatile transcription factor, capable of both
activation and repression by binding directly to DNA at its zinc finger domain or by recruiting chromatin modifiers
to its SET domain to regulate transcription . The DNA-binding domain of PRDM1 is either absent or mutated in
zebrafish mutants and in SHFM families. Therefore, I hypothesize that direct DNA binding through the zinc
finger domain of PRDM1 is necessary for activation of gene expression required for maintaining AER
activity during limb development. The proposed study will test this hypothesis in three focused aims. The first
aim will use a conditional rescue experiment to determine the functionally active domain of Prdm1a (zebrafish
ortholog) during limb development. Constructs of modified prdm1a, in which different domains are deleted, will
be injected into null zebrafish mutants. The second aim will determine where Prdm1a binds to DNA during
pectoral fin bud development. The third aim will test the pathogenicity of each SHFM PRDM1 variant in zebrafish
following mutagenesis by CRISPR-Cas9 and homology directed repair. I will analyze pectoral fin bud
development and DNA binding in each mutant. Together, the results from this study will improve our
understanding of one of the many pathways involved in limb development. It will also provide insight into how
mutations in PRDM1 can lead to congenital limb disorders and help us better predict disease outcomes or
phenotype severity based on the given variant.

## Key facts

- **NIH application ID:** 10067212
- **Project number:** 1F31HD103368-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Brittany Truong
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,720
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067212

## Citation

> US National Institutes of Health, RePORTER application 10067212, Understanding the role of PRDM1 in limb development and split hand/foot malformation. (1F31HD103368-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10067212. Licensed CC0.

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