Mapping of cataract genes in the canine genome and molecular analysis of PAX6 for causal association with cataract, aniridia, and other ocular diseases.

摘要

Cataracts are the leading cause of blindness and low vision throughout the world. Millions of people suffer as a result of this debilitating disease, and millions of dollars are spent annually on cataract removal surgery, which is the only cure. Genes have been identified which cause cataracts when mutated in man and/or mouse. Understanding the functions of these genes, as well as the mechanisms involved in cataract formation may help us to develop ways to prevent, delay, or cure cataracts. Animal models have contributed significantly to our understanding of normal lens development, as well as abnormal development and cataract formation. With the recent advances in canine genomics, the dog has become a promising model for studying the molecular aspects of ocular diseases. Furthermore, inherited cataracts occur in over 20 breeds of dog. The chromosomal locations of 21 genes known to cause cataracts in man, and/or mouse were determined in the canine genome using a Radiation-Hybrid mapping technique. This created a tool which could facilitate association and linkage analysis in canine pedigrees with inherited cataracts. Next, the canine homologue of the cataract-associated gene PAX6 was selected for cloning and characterization, and was found to have remarkable homology with the human gene. Finally, canine PAX6 was evaluated for mutations causing cataract, aniridia, persistent pupillary membranes, sclero-cornea, and choroidal hypoplasia. Direct sequence analysis of PAX6 in affected dogs revealed only single nucleotide polymorphisms and microsatellite changes. However, further pedigree information and analysis is needed to definitively rule out PAX6?s involvement in these ocular diseases.