Highlights from the May 2017 Global Health Vision Lecture
At the May 15 Global Health Vision Lecture, Takeshi Iwata, Ph.D., director of the molecular and cellular biology division at the National Institute of Sensory Organs, Tokyo Medical Center, Japan described efforts to discover new eye disease genes. In 2014, Iwata teamed up with eye researchers in Asia and the NEI to create the Asian Eye Genetics Consortium, a multi-national collaboration to develop and share a database of genetic and clinical information. To date, the consortium has sequenced the genomes of more than 1000 families of which only 17 percent contain previously known retinal disease mutations. More than 80 percent of mutations identified are new to vision scientists. “That is a lot of new genes,” said Iwata.
One of the newly discovered mutations is found in the LRRTM4 (Leucine Rich Repeat Transmembrane 4) gene, and is associated with macular dystrophy. In these patients, the rod cells do not respond to light. Mice carrying the mutation develop too many connections, or synapses, between neurons in the retina.
Another newly discovered mutation, this one in the optineurin gene, is associated with inherited forms of glaucoma and with amyotrophic lateral sclerosis. Optineurin is important for moving vesicles – cellular compartments – around the cell and is involved in cellular recycling. The E50K mutant form of optineurin interacts with many other proteins, including one called PDK1. PDK1 is a kinase, or molecular switch, that is part of a growth signaling pathway. The thinning of the optic nerve that happens in glaucoma can be prevented in mice with the mutation by blocking the interaction between optineurin and PDK1 with an inhibitor of PDK1 – which, happily, is already an FDA-approved drug. Clinical trials are needed to investigate this potential treatment for glaucoma in people.
Although these studies will be foundational for developing new therapies, there are simply too many mutations to study each and every single one individually, said Iwata. By understanding the molecular pathways that produce clinical outcomes, the mutations can be grouped according to function, he said.
Calvin Pang, Ph.D., member of AEGC and the S. H. Ho professor of visual sciences at The Chinese University of Hong Kong and director of the new Shantou International Eye Center, presented his group’s work identifying the underlying mechanisms of complex eye diseases – that is, diseases caused by multiple genes and environmental factors. Polypoidal choroidal vasculopathy (PCV), whose symptoms include blurred or dim vision, develops at a younger age in Asians than in Caucasians and is more common in Asian men than Asian women, said Pang.
Using large studies correlating mutations to clinical outcomes, Pang is beginning to identify the genes underlying these complex diseases – and the genes that account for differences in incidence and severity of the diseases in different populations. “The Mendelian diseases - these genes that we already know - contribute a lot to eye disease, but as time goes on, it’s not sufficient,” said Pang. “We need to know a lot more about the interactions of the genes and variation of the genes.”