Abstract
Purpose :
Heparan-α-glucosaminide N-acetyltransferase (HGSNAT) participates in lysosomal degradation of heparan sulfate. Mutations in the gene encoding this enzyme cause mucopolysaccharidosis IIIC (MPS IIIC) or Sanfilippo disease type C. MPS IIIC is a lysosomal storage disease that causes progressive neurodegeneration in children, leading to dementia and death before adulthood. MPS IIIC patients exhibit incidences of non-syndromic retinitis pigmentosa and early signs of night blindness. The goal of this study was to investigate if retinal degeneration can be detected in the mouse model for MPS IIIC using the Hgsnat knockout (KO) approach.
Methods :
Heterozygous mice carrying mutation in the Hgsnat were crossed and offspring were sacrificed at 6 months of age. Eyes were collected for cryosectioing and characterized for cone and rod photoreceptors using cone arrestin, S-opsin and rhodopsin antibodies. Outer nuclear layer (ONL) thickness and number of nuclei in the ONL were measured at every 0.4 mm distance starting from the optic nerve (n=7). Retinal whole mount preparations were labelled with S-opsin and M-opsin antibodies to assess cone opsin gradient and density.
Results :
Our data suggest that loss of Hgsnat severely affects rod photoreceptors while cone photoreceptors are mainly unaffected at 6 months of age. We observed more than 33% reduction in the ONL thickness and more than 40% reduction in the number of nuclei in the ONL in the Hgsnat KO retinas compared to those of the wild-type controls (P<0.05). Reduction in ONL thickness and number of nuclei indicate rod photoreceptor degeneration. We also observed thinner outer segments in Hgsnat KO retinas indicating reduced levels of rod photo-pigment rhodopsin.
Conclusions :
To our knowledge, these are the first reports of retinal degeneration in the animal model of MPS IIIC. Together our findings indicate that retinal manifestations of MPS IIIC are present even before cerebral manifestations. Thus, ophthalmological evaluations could be used as early diagnostic indicators of disease progression as well as end-points for evaluation of future therapies for MPS IIIC patients.
This is a 2020 ARVO Annual Meeting abstract.