All ETDs from UAB

Advisory Committee Chair

Natalia Y Kedishvili

Advisory Committee Members

Herbert C Cheung

Fang-Tsyr Lin

Kirill M Popov

Philip A Wood

Document Type

Dissertation

Date of Award

2008

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Retinol dehydrogenase 12 (RDH12) is a member of the microsomal short-chain dehydrogenase/reductase superfamily of proteins that is highly expressed in photorecep-tor cells. Mutations in RDH12 are associated with severe early-onset autosomal recessive retinal dystrophy, leading to legal blindness. Disease-associated RDH12 variants exhibit lower protein levels when expressed in eukaryotic cells. However, the physiological role of RDH12 remains unclear. As established previously, RDH12 recognizes both retinoids and lipid peroxidation products (medium-chain aldehydes) as substrates and exhibits the highest catalytic efficiency for all-trans-retinaldehyde. As the main goal of this dissertation, we characterized the catalytic properties of RDH12 and its naturally occurring mutants in vitro and in intact cells. Further, we deter-mined the contribution of RDH12 to retinoid homeostasis and detoxification of lipid per-oxidation. Finally, we determined the biochemical basis for the reduced cellular levels of disease-associated mutants of RDH12. Our findings offer a better understanding of the physiological function of RDH12 in photoreceptor cells and the molecular basis of the disease associated with RDH12 mutations.

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