Allelic variation in the canine Cox-2 promoter causes hypermethylation of the canine Cox-2 promoter in clinical cases of renal dysplasia

BACKGROUND: Novel allelic variants in the promoter of the canine cyclooxygenase-2 (Cox-2) gene are associated with renal dysplasia (RD). These variants consist of either deletions of putative SP1 transcription factor-binding sites or insertions of tandem repeats of SP1-binding sites located in the CpG island just upstream of the ATG translation initiation site. The canine Cox-2 gene was studied because Cox-2-deficient mice have renal abnormalities and a pathology that is strikingly similar to RD in dogs. FINDINGS: The allelic variants were associated with hypermethylation of the Cox-2 promoter only in clinical cases of RD. The wild-type allele was never methylated, even in clinical cases that were heterozygous for a mutant allele. In cases that were biopsy-negative, the promoter remained unmethylated, regardless of the genotype. Methylated DNA was found in DNA from various adult tissues of dogs with clinical RD. CONCLUSIONS: The mechanism of action of the allelic variation in the canine Cox-2 promoter most likely involves variation in the extent of epigenetic downregulation of this gene. This epigenetic downregulation must have occurred early in development because methylated Cox-2 promoter DNA sequences are found in various adult tissues.