Eyeworld

EW CATARACT/IOL 26 April 2011 by Maxine Lipner Senior EyeWorld Contributing Editor Recently discovered YAP protein starting conversation about cataract prevention YAP may provide viable treatment target A newly discovered protein dubbed YAP may one day prove to be a therapeutic target for cataract pre- vention, according to Duojia Pan, Ph.D., professor, Johns Hopkins University, Baltimore, and investigator at the Howard Hughes Medical Institute, Baltimore. Re- search published in the July 2010 issue of Developmental Cell indicated that mutation of this protein could result in a tumor, as well as cataract development. The YAP protein has been shown to suppress NF2 gene activity, which is responsible for regulating tissue size. "We wondered what hap- pens if you remove the equivalent of the NF2 protein in the liver—you get a big liver and develop liver can- cer," Dr. Pan said. "Then we won- dered what happens if you also remove YAP." This tamped down all the tumor activity in the neurofibro- matosis cases and did so when only one copy of the YAP gene was re- moved. Cataract phenotype Investigators initially looked at YAP function in the liver in mice. They then looked at a different system that they thought would perhaps be more relevant to the human dis- ease—the lens. "Over 80% of NF2 patients have cataracts," Dr. Pan said. "We thought, 'This is a good phenotype.'" Investigators were able to show in the mouse that by re- moving the gene function of NF2, they could recreate that cataract phenotype. Dr. Pan and fellow investigators wondered, if the NF2-related cataract is due to too much YAP, would it be possible to suppress the phenotype if YAP is removed? They found that this was indeed possible. "We can suppress all of that cataract phenotype by removing just one copy of YAP, not even two copies," Dr. Pan said. "This lens now looks absolutely normal." Dr. Pan has two not necessarily mutually exclusive theories on what might be occurring here. He pointed out that NF2 is a tumor suppressor and that by definition if you remove that gene, the cells will over-prolifer- ate. "In the lens, if normally Merlin [NF2] is tuning down, the cells pro- liferate a bit; if you remove the brick, these cells proliferate more," Dr. Pan said. "Once they proliferate more they're going to contribute to the ectopic cells—they literally are the cataract." A second possibility is that by removing the NF2 gene, the prop- erty of the cells is changed. "Nor- mally in the lens we know exactly EyeWorld acknowledges the corporate sponsors of EyeWorld Corporate Events at the 2011 ASCRS•ASOA Symposium & Congress Abbott Medical Optics Inc. Alcon Laboratories Inc. Bausch & Lomb Carl Zeiss Meditec Inc. MST OptiMedica Ziemer Ophthalmology continued on page 28

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