Genetics of x-linked and autosomal recessive hereditary nephropathy in the domestic dog

Although typically thought of as a beloved companion or indispensable aide, the domestic dog (Canis lupus familiaris) has emerged as an excellent model for the study of human hereditary diseases. Many hereditary diseases of the dog have nearly identical clinical presentations as those of the human and are, most often, caused by mutations in the same genes. One such disease is hereditary nephropathy; an inherited glomerular disease in the domestic dog that is similar to Alport syndrome of the human. Both diseases are caused by mutations in the type IV collagens genes, and the disease has nearly identical pathology and clinical presentations in the dog and human. By studying this disease in the dog, our laboratory hopes to increase understanding of the disease so that information that can be applied to both the human and the dog. Reported here is 1) the development of a genomic based test to determine genotypes of mixed breed dogs in a colony presenting with X-linked hereditary nephropathy, 2) the determination of patterns of X-chromosome inactivation in normal dogs and dogs that are carriers of Xlinked hereditary nephropathy, 3) the design of a synthetic COL4A5 cDNA to be used for gene therapy treatment of dogs with X-linked hereditary nephropathy, 4) the investigation of type IV collagen gene expression changes in normal dogs and those affected with X-linked and autosomal recessive hereditary nephropathy, and 5) the discovery of the mutation causative for autosomal recessive hereditary nephropathy in the English Cocker Spaniel. Utilization of the colony of dogs affected with X-linked hereditary nephropathy (for which the causative mutation was previously identified) allowed for comparisons of type IV collagen gene expression to English Cocker Spaniels with autosomal recessive hereditary nephropathy. These data were critical to identification of the gene harboring the causative mutation for autosomal recessive hereditary nephropathy. Sequencing was performed to identify the mutation. With the ability to test for carriers of this disease, it is our hope that breeders will use it to to maintain the desired traits in the ECS while simultaneously eliminating the production of affected offspring.