This spontaneous 27 kb deletion includes the chondroitin N-acetygalactosaminyltransferase domain of chondroitin sulphatase 1 and thus disrupts production of the glycosaminoglycan chondroitin sulfate, which is normally present in extracellular matrix and cell surface proteoglycans. Immunohistochemistry using a polyclonal antibody does detect CHSY1 protein in homozygotes. The phenotypic traits of Chsy1skt homozygotes include smaller overall body size, kinked tail, retinal degeneration, inflammatory infiltrates in the kidney, and the development of a hunched posture, hair loss, and hippocampal neurodegeneration with age. Homozygotes are reported to have an average lifespan of only 20 months compared with 27 months for heterozygotes. There is a significant decrease in the number of macrophages in both the bone marrow and spleen and a significant decrease in the number of neutrophils in the bone marrow but not the spleen. The frequencies of lymphocytes and monocytic cells in bone marrow and spleen are reportedly normal.
CHSY1 is found in the retinal photoreceptor inner segments and retinal pigment epithelium, and immunohistochemistry shows a normal expression pattern in Chsy1skt homozygotes, but the chondroitin sulfate glycosaminoglycans that are normally found in the retinal interphotoreceptor matrix and apical surface of the retinal pigment epithelium are absent. By 4 weeks of age the retinal outer nuclear layer of homozygotes shows significant TUNEL staining, increased retinal stress, and increased invasion of activated and transitioning microglia in the outer plexiform layer and the outer nuclear layer. This persists in 8-week-old homozygotes with microglia found in the outer nuclear layer and retinal pigment epithelium. Histology at 8 weeks of age shows ectopic synaptic interactions between photoreceptor cells and bipolar cells, severe disruption of the columnar structures and outer segment tips of the photoreceptor outer segment, and decreased thickness of the outer nuclear layer. Consistent with this photoreceptor cell degeneration, scotopic ERG shows decreased a and b waves at 8 weeks of age. CHSY1 is also expressed in CA1, CA2, and CA3 of the hippocampus, where there is also a decrease in chondroitin sulfate glycosaminoglycans. Assessment at 8 weeks of age and 1.5 years of age found increased numbers of microglia and an increased percentage of microglia that are activated in the CA1, CA2, and CA3 regions of the hippocampus. Hippocampal neurodegeneration is found at 1.5 years of age. (Macke et al., 2020)
