Title:
Genomics, Pathogenesis and Future Therapy of Gelatinous Drop-Like Corneal Dystrophy

Satoshi Kawasaki
Department of Ophthalmology, Osaka University

Abstract:
Gelatinous drop-like corneal dystrophy (GDLD) is a rare hereditary disease characterized by bilateral corneal amyloidosis and is one of the most severe corneal dystrophies. The cornea of GDLD is characterized by multiple protrusions of subepithelial amyloid depositions and increased permeation of tear fluid. The amyloidogenic protein of GDLD was turned out to be tear lactoferrin. Using the technique of linkage analysis and subsequent candidate gene approach, the responsible gene for GDLD was discovered. The gene is the tumor associated calcium transducer 2 (TACSTD2) gene, which encodes a single-pass transmembrane protein. After the discovery, the pathogenesis of GDLD was unveiled. The TACSTD2 protein binds to the claudin (CLDN) 1 and 7 proteins, and protects them from ubiquitin-proteasome degradation. In GDLD cornea, where the TACSTD2 gene is mutated and loses its function at both alleles, the CLDN1 and 7 proteins are degraded, leading to the decrease of tight junction function and eventual amyloid depostion. At present, GDLD cornea is surgically treated by corneal transplantation. However, transplanted corneal epithelial cells are rejected in a brief time. Gene therapy would be the effective treatment for GDLD. For this, theoretical assessment was performed using immortalized corneal epithelial cells derived from a GDLD patient.