Graeme J. Wistow, Ph.D.
Section on Molecular Structure and Functional Genomics
Building 6, Room 106
6 Center Drive
Bethesda, MD 20892-0608
Cataract: The major proteins that confer transparency and focusing power on the eye lens are the crystallins. These proteins are highly adapted for their roles and have fascinating and informative evolutionary histories. They are very stable, lasting for years without turnover while maintaining the necessary organization to keep the lens working as a lens. However, genetic variants or age-related changes can disrupt this organization, causing the proteins to change conformation and aggregate into particles, including amyloid-like fibrils, that can scatter light and make the lens opaque, forming a cataract. We are currently using x-ray crystallography and various spectroscopic techniques to study how the proteins interact normally in the lens and what happens as they aggregate. In particular, we have derived a remarkable high resolution structural model for a crystallin aggregation intermediate. We are also studying a potentially important interaction of γ-crystallins and actin, a major structural and functional component of all cells.
In earlier genomics studies (NEIBank) we discovered two novel lens-specific genes, KLPH and Lengsin. We are exploring their roles in normal lens development and find that deficits in these proteins give rise to focusing defects and age-related cortical cataracts. From its genomic location, Lengsin is a candidate gene for cortical cataract in humans.
AMD: Protein and cholesterol-rich deposits basal to the retinal pigment epithelium (RPE) occur in some common forms of AMD. We have used functional genomics techniques to show that two AMD-related proteins, CFH and Fibulin3, form specific aggregates in eyes with dry AMD. Different Fib3 deposits also occur in wet AMD. We found that RPE cells stressed by serum-deprivation secrete Fib3. Expression studies showed that, over the same period, the cells up-regulate cholesterol synthesis and accumulate cholesterol while also becoming deficient in free zinc. Since serum-starvation of RPE may also occur in AMD, this provides an interesting new model for the progression of the disease, allowing us to test serum components that might help slow the processes that lead to vision loss.
Studies on Retbindin, a novel photoreceptor-specific gene we discovered through NEIBank, have shown it has an important role in maintaining normal retina function and its deletion causes severe age-related defects in mouse retina with features reminiscent of AMD.
Other work: We also collaborate with colleagues on other aspects of eye development and function. Recent work defined an essential role for a cluster of regulatory micro-RNAs (miR-183C) in the maturation of photoreceptors and other sensory neurons.
Sagar V, Chaturvedi SK, Schuck P, Wistow G. Crystal Structure of Chicken γS-Crystallin Reveals Lattice Contacts with Implications for Function in the Lens and the Evolution of the βγ-Crystallins. Structure. 2017;25(7):1068-1078.e2.
Rajapakse D, Peterson K, Mishra S, Wistow G. Serum starvation of ARPE-19 changes the cellular distribution of cholesterol and Fibulin3 in patterns reminiscent of age-related macular degeneration. Exp Cell Res. 2017;361(2):333-341.
Fan J, Jia L, Li Y, Ebrahim S, May-Simera H, Wood A, Morell RJ, Liu P, Lei J, Kachar B, Belluscio L, Qian H, Li T, Li W, Wistow G, Dong L. Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse. Proc Natl Acad Sci U S A. 2017;114(21):E4271-E4280.
Chen Y, Sagar V, Len HS, Peterson K, Fan J, Mishra S, McMurtry J, Wilmarth PA, David LL, Wistow G. γ-Crystallins of the chicken lens: remnants of an ancient vertebrate gene family in birds. FEBS J. 2016;283(8):1516-30.
Wyatt MK, Tsai JY, Mishra S, Campos M, Jaworski C, Fariss RN, Bernstein SL, Wistow G. Interaction of complement factor h and fibulin3 in age-related macular degeneration. PLoS One. 2013;8(6):e68088.
Related Scientific Focus Areas
Genetics and Genomics
Molecular Biology and Biochemistry
This page was last updated on August 20th, 2018