Molecular Genetics of Color Vision

University Of Washington, Seattle WA

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Abstract

The long-term objectives of this proposal are to fully define the molecular genetics of human color vision and its common defects, and to elucidate the mechanisms of regulation of expression of the X-linked red-green color vision locus. A remarkable heterogeneity of genotypes and phenotypes exist at this locus due to the existence of common spectral variants of the long wave sensitive (L) and middle wave sensitive (M) pigments causing various color vision defects. Preliminary studies have shown that some women who carry three forms of the L and M pigment genes have additional color discrimination capacity. We will investigate the genetic basis for this extended color discrimination capacity. Using the human retinoblastoma cell line WERI, we found that thyroid hormone regulates expression of the L and M pigment genes plus several others that are involved in photoreceptor development and/or human retinal diseases. We plan to validate these findings in vivo using a thyroid hormone receptor [unreadable]2 (TR[unreadable]2) knockout mouse. We will perform expression microarray anslysis in the retinas of these mice at different stages of development. The results of this analysis will identify the gene(s) that acts as an intermediate in regulation of opsin gene expression by TR[unreadable]2 during development. We identified an interesting region upstream of the M-pigment gene which is homologous to [unreadable]insulators[unreadable] that have been shown to control gene expression. A polymorphism in this potential [unreadable]insulator[unreadable] region is associated with human L:M cone ratio. We will test the hypothesis that this is really an insulator that plays an important regulator of expression of the L and M cone opsins. In addition, we will define and characterize all of the rest of the regulatory regions of this locus by high resolution/high throughput DNase I hypersensitivity scans. These studies will provide new insights into the molecular mechanisms of regulating photoreceptor genes, and in turn will help in understanding the relationship between defects in gene expression and retinal disease. This will also help in developing cell-specific gene therapy strategies.