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PRODUCED BY AND FOR MEMBERS OF THE DEPARTMENT OF SURGERY May 2013 | Archived Issues

Cedars-Sinai Researchers Identify Genes Contributing to Corneal Blindness

Keratoconus is a disease of the eye in which the cornea progressively thins, resulting in mixed myopic astigmatism. Approximately 20 percent of patients become legally blind and require corneal transplantation, making it one of the most common causes for corneal transplantation in young adults worldwide.

Funded by the National Eye Institutes of Health for the past 20 years, Yaron S. Rabinowitz, MD (pictured at right), corneal transplant surgeon, director of Ophthalmology Research at Cedars-Sinai and a member of the Department of Surgery, has been the leading researcher in the world on keratoconus focusing on unraveling the genes that may contribute to the development of this disease and devising techniques for early detection using sophisticated computer modeling and optical coherence tomography. His review article on keratoconus published in 1998 is the most quoted article on the subject in the medical literature and according to Google Scholar has been cited by his peers approximately 1,000 times.

His group, in collaboration with the Medical Genetics group at Cedars-Sinai, has made several significant discoveries this year that might provide clues as to the underlying mechanisms causing the disease. In a genomewide association study of patients with keratoconus, his group discovered an association with the RAPGAB gene suggesting a defect in the control of the development of the eye. This finding was published in the journal Human Molecular Genetics (reference 1 below).

Illustrations show a normal cornea and the corneal thinning caused by keratoconus.

In its advanced stages, keratoconus can cause scarring on the cornea.

Two additional publications in the journal Investigative Ophthalmology & Visual Science (reference 2 and reference 3 below) describe their discoveries as it relates to the collagen fibers that span the cornea. One article suggests that there is a defect in the cross links between the collagen fibers resulting in weakening and bulging of the cornea, while the other article suggests that there is a defect in collagen 5A, which controls collagen assembly of the fibers in the cornea, thereby weakening the cornea and resulting in the development of keratoconus.

In January of this year, in collaboration with an Australian research group and a consortium of roughly 50 centers worldwide, Rabinowitz's group identified several gene loci that are associated with regulating central corneal thickness. These findings were published in the journal Nature Genetics (reference 4 below).

In collaboration with the Cedars-Sinai Regenerative Medicine Institute, Rabinowitz and his collaborators are developing stem cells from the corneal stroma and using a disease-modeling approach. They hope to learn more about the role of genes in the early and late development of keratoconus. It is hoped that these new findings will lead to further translational discoveries, which may allow for a medical cure for keratoconus and thus obviate the need for future corneal transplantation.

References

1. Li X, Bykhovskaya Y, Haritunians T, Siscovick D, Aldave A, Szczotka-Flynn L, Iyengar SK, Rotter JI, Taylor KD, Rabinowitz YS. "A genomewide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries." Human Molecular Genetics, 2012 Jan 15;21(2):421-9

2. Li X, Bykhovskaya Y, Haritunians T, Siscovick D, Aldave A, Szczotka-Flynn L, Iyengar SK, Rotter JI, Taylor KD, Rabinowitz YS. "Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus." Invest. Ophthalmol. Vis. Sci., 2013 March 19, 10.1167/iovs.13-11601

3. Bykhovskaya Y, Li X, Epifantseva I, Haritunians T, Siscovick D, Aldave A, Szczotka-Flynn L, Iyengar SK, Taylor KD, Rotter JI, Rabinowitz YS. "Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies." Invest. Ophthalmol. Vis. Sci., 2012 Jun 28;53(7):4152-7

4. Lu Y, Vitart V, Burdon KP, Khor CC, Bykhovskaya Y, Hauser MA, Rabinowitz YS, Pfeiffer N, Mackey DA, Craig JE, Macgregor S, Wong TY. "Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus." Nature Genetics, 2013 Feb;45(2):155-63