# Vision defects associated with loss of C-Vps function

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2021 · $373,450

## Abstract

ABSTRACT
Leukodystrophies (LD) and genetic Leukoencephalopathies (gLE) are genetic disorders affecting the white
matter (myelin) in the central nervous system. LDs and gLEs progressively affect the motor and sensory
systems, including the visual systems. Parents of affected children first note visual problems as a gradual loss
in the ability of their child/children to track visual cues. Vision slowly worsens over subsequent years, likely due
to the loss of myelin in the optic nerve and brain, termed cortical blindness. An MRI is typically diagnostic for
myelination defects, but a clear diagnosis of disease-specific LDs and gLEs remains a challenge, and the
majority of LDs and gLEs have an unknown genetic origin. We recently identified a mutation in VPS11 as a
causative allele in the gLE phenotypes observed in five individuals from three unrelated Ashkenazi Jewish (AJ)
families. Our analysis indicates a carrier rate of 1:250 AJ individuals. VPS11 functions in a complex of four C-
VPS proteins, which are conserved from yeast to humans, and control critical cellular processes in the
endolysosomal and autophagy pathways. These processes are only beginning to be investigated at the
molecular level, mainly in yeast. Indeed, prior to our recent report, there were no known human mutations of
any of the C-VPS proteins. However, we previously characterized a zebrafish vps11 mutant and have recently
discovered that it shares many of the phenotypes of the human mutant, including defects in endolysosomal
and autophagy pathways, myelination defects in the CNS, loss of retinal and CNS neurons, and motor defects.
This proposal aims to take advantage of the zebrafish model to characterize the pathology underlying the
vision loss associated with loss of C-Vps function. Aim 1 will further characterize the vision and motor defects
associated with loss of Vps11 function in our zebrafish model and characterize the gLE phenotypes associated
with loss of other C-Vps proteins. Aim 2 will analyze the intercellular consequences of the specific VPS11
mutation that underlies the gLE phenotypes and screen for compounds that will rescue the autophagy flux
defects associated with this disease. Aim 3 utilizes a mammalian cell culture model to co-culture
oligodendrocytes and neurons to test the role of VPS11 in myelin formation, which is the first investigation of
VPS11 function in oligodendrocytes in any species. By combining mammalian in vitro techniques with the
power of the zebrafish mutant model, the successful completion of these aims will significantly advance our
long-term goal of elucidating the mechanism that underlies VPS11-mediated vision loss.

## Key facts

- **NIH application ID:** 10133076
- **Project number:** 5R01EY026551-05
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Ryan Thummel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,450
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133076

## Citation

> US National Institutes of Health, RePORTER application 10133076, Vision defects associated with loss of C-Vps function (5R01EY026551-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133076. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*