With a series of clinical, genetic, bioinformatic and biochemical experiments, we describe here two genetically different forms of retinal degeneration in the MS breed mapping to chromosomes 15 and X. We identify a novel fully penetrant recessive silencer variant in chromosome 15 with a possible gain-of-function effect resulting in overexpression of two retinal target genes, EDN2 and COL9A2. Our results provide a new spontaneous dog model for retinal pathophysiology and insights to retinal biology and gene regulation. The gene discussed is EDN2; the disease is retinal degeneration.