# A multi-species approach to find regulators of deafness genes

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $423,826

## Abstract

PROJECT SUMMARY
Genetic screens in mice and the naturally occurring genetic variation in humans have provided a valuable
resource to identify genes implicated in hair cell function and deafness. Two examples is the identification of
genes involved in Usher syndrome, the most common form of deaf-blindness, and the role of Myh9 in both
syndromic and non-syndromic deafness. We have used the power of Drosophila genetics to identify new
genes involved in hearing and deafness. The auditory organs of Drosophila and vertebrates have a number of
molecular and functional similarities despite being widely separated in evolutionary time. We identified
mutations in Ubr3, an E3 ubiquitin ligase, that cause a physical detachment of the sensory components of
Johnston's organ from the fly antenna. Strikingly, this phenotype is identical to that seen in mutations in
Drosophila Myosin VIIa. Since Myosin VIIa mutations in humans cause Usher Syndrome type IB, it is possible
that Ubr3 may regulate Myosin VIIa function in invertebrates and vertebrates. Our data suggest that Ubr3
genetically interacts with Myosin VIIa and Ubr3 and Myosin VIIa physically and genetically interact with
Drosophila homologues of two other Usher syndrome proteins, PCDH15 and Sans. However, we have found
that Ubr3 does not modify Myosin VIIa, but instead mono-ubiquitinates non-muscle Myosin II. This modification
increase an interaction between the two myosins, and fine-tuning the level of this interaction appears critical for
Myosin VIIa function.
In the present proposal, we will expand on the use of Drosophila as a model system to understand deafness by
characterizing the roles of Ubr3, Myosin II and Myosin VIIa in hearing in Drosophila (Aim 1). We will then test
the function of Ubr3 in the development and function of mouse hair cells, and will test whether the interaction of
Myosin II and Myosin VIIa is conserved in mice (Aim 2). Finally, we will carry out a genetic screen of 3000
Drosophila genes that may be involved in human disease using newly developed protein knockdown
technology to identify genes that play a role in hearing in Drosophila (Aim 3).

## Key facts

- **NIH application ID:** 9823876
- **Project number:** 5R01DC014932-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Andrew K Groves
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,826
- **Award type:** 5
- **Project period:** 2016-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9823876

## Citation

> US National Institutes of Health, RePORTER application 9823876, A multi-species approach to find regulators of deafness genes (5R01DC014932-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9823876. Licensed CC0.

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