# Developmental models to determine the molecular mechanisms that cause MYH9-related diseases

> **NIH NIH R03** · UNIVERSITY OF WISCONSIN MILWAUKEE · 2021 · $76,000

## Abstract

This proposal aims to develop vertebrate models to elucidate molecular mechanisms by which known
mutations in MYH9 disrupt development. There are five diseases that result from mutations in MYH9, including
clinical syndromic disorders that are classified as MYH9-related diseases: May-Hegglin anomaly, Sebastian,
Fetchner, and Epstein syndrome; and non-syndromic deafness DFNA17. These diseases share common
mutations in the MYH9 gene and are characterized by a number of symptoms including platelet abnormalities,
nephritis, visual defects, and hearing loss. MYH9 encodes for the highly conserved non-muscle myosin IIA
protein (NMIIA), which has essential roles in cell division, cell migration, and cell shape changes. However,
there is a critical gap in the understanding of how MYH9 mutations found in the human population contribute to
the etiology of MYH9-related diseases. We propose to generate zebrafish (Danio rerio) models of the most
common MYH9 mutations to examine the development of the organs that are affected in MYH9-related
disease, particularly the ear, eye, and kidney. Zebrafish models will provide distinct advantages over current
mammalian models in the ability to access and examine early organ development at single-cell resolution
using live imaging. Zebrafish embryos are optically transparent, have rapid development, and genome editing
techniques in zebrafish are well established. Our long-term research goal is to determine the molecular
mechanisms for how mutations in the MYH9 gene lead to MYH9-related diseases. As the first step towards our
long-term research goal, the overall objective of this R03 proposal is to establish zebrafish models and
transgenic lines to study the mechanisms that cause MYH9-related diseases. Our central hypothesis is that
zebrafish models of conserved MYH9 mutations and NMIIA-labeled transgenic lines can be generated and will
allow us to elucidate the molecular mechanisms that cause MYH9-related diseases. We will test our central
hypothesis by pursuing the following specific aims. Aim 1 is to generate myh9 mutant zebrafish lines with
targeted and specific mutations that correspond to the most common human mutations in MYH9-related
diseases. Aim 2 is to create transgenic zebrafish lines with endogenously labelled NMIIA protein to examine
NMIIA localization and dynamics during development. We will accomplish these aims by generating zebrafish
models of MYH9 mutations using CRISPR/Cas9 genome editing. The proposed work is innovative and
significant because these studies will establish developmental vertebrate models that are needed to investigate
and identify the role for mutations in the highly conserved MYH9 gene and determine the molecular
mechanisms for how these mutations cause MYH9-related diseases. The outcomes from this proposal are
expected to have an important positive impact because they will provide the tools necessary to define how
mutations in MYH9 lead to developmental defects.

## Key facts

- **NIH application ID:** 10077874
- **Project number:** 5R03HD094034-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN MILWAUKEE
- **Principal Investigator:** Jennifer H Gutzman
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $76,000
- **Award type:** 5
- **Project period:** 2020-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077874

## Citation

> US National Institutes of Health, RePORTER application 10077874, Developmental models to determine the molecular mechanisms that cause MYH9-related diseases (5R03HD094034-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10077874. Licensed CC0.

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