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

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY023666-03
Application #
9084603
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Bhardwaj, Pooja; Hans, Amrita; Ruikar, Kinnari et al. (2018) Reduced Chlorhexidine and Daptomycin Susceptibility in Vancomycin-Resistant Enterococcus faecium after Serial Chlorhexidine Exposure. Antimicrob Agents Chemother 62:
Adams, Hannah M; Joyce, Luke R; Guan, Ziqiang et al. (2017) Streptococcus mitis and S. oralis Lack a Requirement for CdsA, the Enzyme Required for Synthesis of Major Membrane Phospholipids in Bacteria. Antimicrob Agents Chemother 61:
Tang, Shuang; Fang, Yi; Huang, Gang et al. (2017) Methionine metabolism is essential for SIRT1-regulated mouse embryonic stem cell maintenance and embryonic development. EMBO J 36:3175-3193
Elharar, Yifat; Podilapu, Ananda Rao; Guan, Ziqiang et al. (2017) Assembling Glycan-Charged Dolichol Phosphates: Chemoenzymatic Synthesis of a Haloferax volcanii N-Glycosylation Pathway Intermediate. Bioconjug Chem 28:2461-2470
Guan, Ziqiang; Chen, Lingli; Gerritsen, Jacoline et al. (2016) The cellular lipids of Romboutsia. Biochim Biophys Acta 1861:1076-1082
Guan, Ziqiang; Delago, Antonia; Nußbaum, Phillip et al. (2016) N-glycosylation in the thermoacidophilic archaeon Sulfolobus acidocaldarius involves a short dolichol pyrophosphate carrier. FEBS Lett 590:3168-78
Li, Chijun; Tan, Brandon K; Zhao, Jinshi et al. (2016) In Vivo and in Vitro Synthesis of Phosphatidylglycerol by an Escherichia coli Cardiolipin Synthase. J Biol Chem 291:25144-25153
Liu, Tan; Wen, Rong; Lam, Byron L et al. (2015) Depth-resolved rhodopsin molecular contrast imaging for functional assessment of photoreceptors. Sci Rep 5:13992
Lukose, Vinita; Whitworth, Garrett; Guan, Ziqiang et al. (2015) Chemoenzymatic Assembly of Bacterial Glycoconjugates for Site-Specific Orthogonal Labeling. J Am Chem Soc 137:12446-9
Zein, Wadih M; Jeffrey, Brett G; Wiley, Henry E et al. (2014) CNGB3-achromatopsia clinical trial with CNTF: diminished rod pathway responses with no evidence of improvement in cone function. Invest Ophthalmol Vis Sci 55:6301-8

Showing the most recent 10 out of 12 publications