Retinal degeneration is a major cause of blindness, yet no effective treatments are available. It is estimated that one in 3,500 to 4,000 people is affected by retinitis pigmentosa (RP), a group of inherited retinal degenerative disorders. We recently identified a novel RP-causing mutation in the gene that encodes DHDDS (dehydrodolichol diphosphate synthase), a key enzyme of dolichol biosynthesis. A single base c.124A>G mutation changes the highly conserved Lys42 in DHDDS to a Glu residue, resulting in weak substrate binding and lowered catalytic efficiency. This mutation accounts for 12% of all the autosomal recessive RP cases in Ashkenazi Jewish (AJ) patients and is heterozygous in 1 in 322 in the AJ population. A large knowledge gap exists in our understanding of the link between the DHDDS mutation and retinal degeneration. For example, the exact biological functions of free dolichols, the final products of DHDDS, are not well understood. This mutation provides a rare opportunity to study the roles of free dolichols in photoreceptors. In addition, th molecular and clinical insights obtained from our studies will help to develop novel therapies. Two Hypotheses are proposed: 1) The K42E DHDDS mutation alters dolichol profile and causes dolichol deficiency in photoreceptors, leading to retinal degeneration;2) Free dolichols play essential roles in the structure and functions of photoreceptors, including membrane trafficking and vesicle fusion, which is vitally important in outer segment (OS) morphogenesis, renewal, and synaptic transmission. We also propose 3 Specific Aims to test these hypotheses: 1) Study the effect s of DHDDS mutations on dolichol metabolism in human;2) Study the mechanism of retinal degeneration caused by the DHDDS mutation in mouse;3) Study the biological functions of free dolichols in photoreceptors. We will study dolichol metabolism in fibroblasts, as well as blood and urine from patients. We will also use a mouse model that harbors the K42E DHDDS mutation to understand retinal degeneration caused by dolichol deficiency, and the structural and functional roles of dolichols in photoreceptors. Through the proposed work, we will gain an understanding of the disease process and mechanism caused by DHDDS mutations, and the functions of free dolichols in photoreceptors, with the ultimate goal of developing novel and effective therapies.

Public Health Relevance

We recently identified a novel mutation in the gene encoding dehydrodolichol diphosphate synthase (DHDDS) that causes retinal degeneration, which accounts for 12% of all the autosomal recessive RP in Ashkenazi Jewish (AJ) patients, and 1 out of 322 is a carrier of this mutation in the normal AJ population. In the proposed work, we will analyze skin fibroblasts, blood and urinary samples from patients, and mouse models to study the disease. We will also use mouse models to investigate the molecular and cellular mechanisms of this disease as well as to characterize its natural history and pathogenesis. The ultimate goals are to discover diagnostic biomarkers and develop treatment strategies

National Institute of Health (NIH)
National Eye Institute (NEI)
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Special Emphasis Panel (DPVS)
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Shen, Grace L
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University of Miami School of Medicine
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Coral Gables
United States
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