The RD paper…Posted: February 22, 2011
is now online. It will be 15 years in June since Gabrielle was diagnosed with Renal Dysplasia, beginning our quest for knowledge and our dedication for a useful tool for breeders.
Peer-reviewed and published online at the Public Library of Science, I am very proud to be one of the co-authors on this paper.
1 DOGenes Inc., Peterborough, Ontario, Canada, 2 Department of Clinical Sciences, Tufts Cummings School of Veterinary Medicine, North Grafton, Massachusetts, United States of America, 3 American Lhasa Apso Club, Conifer, Colorado, United States of America
Renal dysplasia (RD) in dogs is a complex disease with a highly variable phenotype and mode of inheritance that does not follow a simple Mendelian pattern. Cox-2 (Cyclooxgenase-2) deficient mice have renal abnormalities and a pathology that has striking similarities to RD in dogs suggesting to us that mutations in the Cox-2 gene could be the cause of RD in dogs. Our data supports this hypothesis. Sequencing of the canine Cox-2 gene was done from clinically affected and normal dogs. Although no changes were detected in the Cox-2 coding region, small insertions and deletions of GC boxes just upstream of the ATG translation start site were found. These sequences are putative SP1 transcription factor binding sites that may represent important cis-acting DNA regulatory elements that govern the expression of Cox-2. A pedigree study of a family of Lhasa apsos revealed an important statistical correlation of these mutant alleles with the disease. We examined an additional 22 clinical cases from various breeds. Regardless of the breed or severity of disease, all of these had one or two copies of the Cox-2 allelic variants. We suggest that the unusual inheritance pattern of RD is due to these alleles, either by changing the pattern of expression of Cox-2 or making Cox-2 levels susceptible to influences of other genes or environmental factors that play an unknown but important role in the development of RD in dogs.
We wish to thank J. Kassis for careful review of the manuscript. The authors wish to dedicate this work to the late Dr. John B. Armstrong, canine geneticist and poodle fancier. He gave much of his time to educate the breeders and owners of purebred dogs about the importance of genetic diversity. His careful analysis of Poodle and Lhasa apso pedigrees with respect to RD were invaluable in the inception of this research. The authors pay tribute to Chiata, a Lhasa Apso who opened the door to discovery. We are grateful to the many dog owners who submitted DNA samples for this study.