The long-term goal of this research program is to understand the role of amino acid sequence polymorphisms in the long- and middle-wavelength cone opsins in vision disorders. All known amino acid substitutions observed in human rhodopsin or in the human S cone opsin are associated with photoreceptor abnormalities and disease. The question we will address in this proposal is - what is the role of amino acid substitutions in the L and M cone opsins in vision disorders? We propose the following specific aims:
Specific Aim 1 : Examine the relationship between cone opsin variants and age related macular degeneration (AMD). Using DNA samples from several hundred subjects with AMD and several hundred matched control subjects we will quantify the association between sequence variations in the L and M opsin genes and risk of AMD.
Specific Aim 2 : A high frequency opsin variant, designated LVAVA, has never been observed in a male with normal vision. Its occurrence is always associated with vision disorder. Individuals with this variant exhibit pathological myopia, cone ERG abnormalities and optic nerve hypoplasia indicating a reduced number of ganglion cells. We will examine the effects of the LVAVA variant on the structure and physiology of cone photoreceptors and other retinal cells in a mouse model and determine the mechanism by which the variant opsin produces its wide spectrum of abnormalities in the eye.
Specific Aim 3 : A second cone opsin variant which is never observed in males with normal vision, designated LIAVA, is generated at a high rate. Function is disrupted in cones expressing this variant and adaptive optics imaging demonstrates that cones expressing it are damaged or lost. We will examine the effects of the LIAVA mutation on the structure and physiology of cone photoreceptors in a mouse model and determine the mechanism by which the variant opsin disrupts photoreceptor function.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Neuhold, Lisa
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University of Washington
Schools of Medicine
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Greenwald, Scott H; Kuchenbecker, James A; Rowlan, Jessica S et al. (2017) Role of a Dual Splicing and Amino Acid Code in Myopia, Cone Dysfunction and Cone Dystrophy Associated with L/M Opsin Interchange Mutations. Transl Vis Sci Technol 6:2
Davidoff, Candice; Neitz, Maureen; Neitz, Jay (2016) Genetic Testing as a New Standard for Clinical Diagnosis of Color Vision Deficiencies. Transl Vis Sci Technol 5:2
Neitz, Maureen; Neitz, Jay (2014) Curing color blindness--mice and nonhuman primates. Cold Spring Harb Perspect Med 4:a017418
Greenwald, Scott H; Kuchenbecker, James A; Roberson, Daniel K et al. (2014) S-opsin knockout mice with the endogenous M-opsin gene replaced by an L-opsin variant. Vis Neurosci 31:25-37
McClements, Michelle; Davies, Wayne I L; Michaelides, Michel et al. (2013) Variations in opsin coding sequences cause x-linked cone dysfunction syndrome with myopia and dichromacy. Invest Ophthalmol Vis Sci 54:1361-9
McClements, Michelle; Davies, Wayne I L; Michaelides, Michel et al. (2013) X-linked cone dystrophy and colour vision deficiency arising from a missense mutation in a hybrid L/M cone opsin gene. Vision Res 80:41-50
Baraas, Rigmor C; Hagen, Lene A; Dees, Elise W et al. (2012) Substitution of isoleucine for threonine at position 190 of S-opsin causes S-cone-function abnormalities. Vision Res 73:1-9
Carroll, Joseph; Dubra, Alfredo; Gardner, Jessica C et al. (2012) The effect of cone opsin mutations on retinal structure and the integrity of the photoreceptor mosaic. Invest Ophthalmol Vis Sci 53:8006-15
Neitz, Jay; Neitz, Maureen (2011) The genetics of normal and defective color vision. Vision Res 51:633-51
Carroll, Joseph; Rossi, Ethan A; Porter, Jason et al. (2010) Deletion of the X-linked opsin gene array locus control region (LCR) results in disruption of the cone mosaic. Vision Res 50:1989-99

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