# IMPDH structure and function in retinal degeneration

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2021 · $214,006

## Abstract

Project Summary
Many different genes and mutations have been associated with photoreceptor degeneration. This enormous
genetic heterogeneity requires the development of treatment approaches targeting common mechanisms and
pathways, which can effectively treat a condition regardless of the underlying genetic cause. Mutations in several
genes involved in guanine nucleotide homeostasis lead to photoreceptor degeneration, likely due to the unique
metabolic demands for cyclic GMP in photoreceptor signaling. Despite this critical importance, basic aspects of
regulation of purine metabolism in photoreceptors have not been investigated rigorously. This proposal is
focused on the critical role of IMP dehydrogenase 1 (IMDPH1), the enzyme that regulates flux through the parallel
de novo adenine and guanine nucleotide biosynthesis pathways. Nine different missense mutations in IMPDH1
are associated with dominant forms of retinitis pigmentosa or Lebers congenital amaurosis, each with varying
severity of disease phenotype. None of the mutations has a direct effect on the intrinsic biochemical activity of
the enzyme, and the mutations do not have deleterious effects in tissues other than the retina. For many years
progress has been stalled on the molecular mechanism of IMPDH1-induced retinopathies due to a lack of animal
models to study the disease pathology, and the lack of a clear defect at the enzyme level. IMDPH forms micron-
scale dynamic filaments both in vitro and in vivo in response to increased demand for guanine nucleotides. We
have now discovered that the IMPDH1 retinal degeneration mutations have a direct effect on the filament form,
either promoting constitutive assembly or preventing polymerization entirely, with concomitant defects in
allosteric regulation of the enzyme activity. Here, we propose a collaborative and initial effort to define the
structure, function, and metabolic role of IMPDH1 in healthy photoreceptors and in transgenic animals that
express IMPDH1 mutant alleles associated with photoreceptor degeneration. Our multidisciplinary approach
combines cryoEM structural analysis with imaging and metabolic measurements in intact retinas. Our work will
provide novel insight into the unique role of IMPDH1 in photoreceptors, and lay the groundwork for analyzing
more mutations and for future targeted therapies to prevent blindness due to cell death.

## Key facts

- **NIH application ID:** 10126019
- **Project number:** 5R21EY031546-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Susan E Brockerhoff
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $214,006
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126019

## Citation

> US National Institutes of Health, RePORTER application 10126019, IMPDH structure and function in retinal degeneration (5R21EY031546-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10126019. Licensed CC0.

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