Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Genetics and Genomics


English (en)

Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Shiming Chen


Cone-rod homeobox: CRX) protein is a "paired-like" homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa: RP), Cone-Rod Dystrophy: CoRD) and Leber Congenital Amaurosis: LCA), with variable severity. The goal of my dissertation project was to develop and characterize animal models to understand genetic mechanisms of phenotypic diversity in CRX-associated disease. Heterozygous Crx Knock-Out: KO) mice: "+/-") have normal vision as adults and fail to model the dominant human disease.

We generated two Crx Knock-IN: K-IN) mouse models: CrxE168d2: "E168d2") and CrxR90W: "R90W"), which carry distinct types of mutations and are associated with retinopathies of differing severity. As seen in human patients, heterozygous E168d2: "E168d2/+") but not R90W: "R90W/+") mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration. Careful morphological and biochemical characterization of K-IN mice and their associated mutant CRX proteins reveals that they cause disease through distinct molecular mechanisms. Unexpectedly, we also identified that E168d2/+ mice express more mutant CRX protein than wild-type CRX resulting in an allelic imbalance favoring the mutant protein. Characterization of a Crx mutant feline model, CrxRdy, in vivo and several Crx mutants in vitro reveals CRX overexpression may be a conserved mechanism. E168d2neo/+, a subline of E168d2 with reduced mutant allele expression, displays a much milder retinal phenotype, demonstrating mutant allele expression level may be a critical genetic modifier of disease severity. Our studies indentify genetic mechanisms contributing to phenotypic diversity of CRX-associated disease, improve understanding of disease pathology and allow for the preliminary testing of novel therapeutic approaches.


Permanent URL: