# Role of a dual splicing and amino acid code in myopia, cone dysfunction and cone dystrophy associated with L/M opsin interchange mutations

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $441,250

## Abstract

The long-term objective of this research is to understand the mechanism by which intermixing of the human
long- (L) and middle- (M) wavelength cone photopigment genes give rise to variants that cause aberrant pre-
messenger RNA (mRNA) splicing, and lead to vision loss with a diverse set of clinical phenotypes. 95% of our
cones are L or M cones, and except at very low light levels when rods are active, all vision is based on cones.
The L and M cones play a critical role in the visually guided feedback mechanism responsible for controlling
eye growth (emmetropization). Every aspect of seeing, including high acuity and color vision, depends on the L
and M cone photopigments and these genes are important risk factors in common eye disorders that plague
modern humans. The L and M (LM) cone photopigment genes, designated OPN1LW and OPN1MW,
respectively, exhibit high haplotype diversity in exons 2, 3 and 4. The most is known about two variants,
designated LIAVA and LVAVA that are associated with photoreceptor dysfunction and severe vision
impairment. They are found in patients with a range of clinical diagnoses including high grade myopia, blue
cone monochromacy and cone dystrophy. We and others have recently shown that combinations of single
nucleotide polymorphisms (SNPs) associated with these variants cause aberrant pre-mRNA splicing. Our
preliminary data show that different combinations of the exon 3 polymorphisms shift the ratio of full length to
exon 3 skipped mRNA, producing variability in the severity of the splicing defect that will be extremely useful in
elucidating the fundamental mechanisms controlling splicing of this exon. Preliminary data obtained using a
cell culture-based splicing assay also suggests that haplotypes of exon 3 that yield moderate levels of exon 3
skipping are associated with an average -1.3 diopters of refractive error compared to low/non-skipping
variants. The pathophysiology of the different mutations is complex because superimposed on the effects of
subnormal amounts of opsin protein produced by the splicing defects, are the effects of some combinations of
the amino acids on protein function. To achieve our goal we propose:
Aim 1: To investigate the role of combinations of SNPs in exons 2, 3 and 4 of the L and M opsin genes in
 splicing by
 1.1 fully enumerating the transcript isoforms, and measuring their relative abundances.
 1.2 investigating and quantitating the effects of exon 3 haplotypes on splicing in cone photoreceptors
 and particularly those haplotypes that are risk alleles for juvenile onset myopia.
Aim 2: To investigate the mechanism of exon 3 skipping using biochemical and molecular biology approaches
Aim 3: To evaluate the potential for exon specific U1 snRNAs to rescue the exon 3 skipping phenotype.

## Key facts

- **NIH application ID:** 9893919
- **Project number:** 5R01EY028118-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** MAUREEN E NEITZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,250
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893919

## Citation

> US National Institutes of Health, RePORTER application 9893919, Role of a dual splicing and amino acid code in myopia, cone dysfunction and cone dystrophy associated with L/M opsin interchange mutations (5R01EY028118-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9893919. Licensed CC0.

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