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Clin Epigenetics. 2014 Apr 3;6(1):7. doi: 10.1186/1868-7083-6-7.
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.
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.
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.
犬环氧化酶-2（Cox-2）基因启动子中的新型等位基因变异与肾发育不良（RD）有关。这些变异包括假定的 SP1 转录因子结合位点的缺失或位于 ATG 翻译起始位点上游的 CpG 岛中 SP1 结合位点串联重复的插入。研究犬 Cox-2 基因是因为 Cox-2 缺陷型小鼠具有肾脏异常，其病理学与犬 RD 非常相似。
等位基因变异仅与 RD 的临床病例中 Cox-2 启动子的高甲基化有关。野生型等位基因从未被甲基化，即使在突变等位基因杂合的临床病例中也是如此。在活检阴性的病例中，无论基因型如何，启动子仍保持未甲基化。在具有临床 RD 的犬的各种成年组织的 DNA 中发现了甲基化 DNA。
犬 Cox-2 启动子中等位基因变异的作用机制很可能涉及该基因表观遗传下调程度的变化。这种表观遗传下调一定是在早期发育过程中发生的，因为在各种成年组织中都发现了甲基化的 Cox-2 启动子 DNA 序列。
