A Drosophila model for Sanfilippo Syndrome

Sanfilippo syndrome (Mucopolysaccharidosis Type III, MPS III) is a rare, autosomal recessive disorder, caused by a deficiency in enzymes involved in the breakdown of heparan sulfate. The disease is characterized by the accumulation of heparan sulfate in lysosomes, which leads to degeneration of the central nervous system. Patients exhibit developmental regression, hyperactivity, sleep irregularity, coarse features and a reduced lifespan. The genome of Drosophila melanogaster contains conserved orthologs of human disease genes. We obtained Drosophila lines with CRISPR-Cas9 generated deletions of fly orthologs of SGSH and NAGLU, mutations in which cause MPS IIIA and MPS IIIB. A deletion in CG14291, which is orthologous to SGSH, displayed phenotypes reminiscent of human Sanfilippo Syndrome. Flies of this line showed reduced lifespan (-28.8%, males; -15.1%, females) and reduced productivity (-78.7% at 2 weeks old) compared to the control. Males of this line exhibited a significant increase in average activity (p<0.0001) and showed impaired phototaxis compared to the control. Thus, the CG14291 deletion line can serve as a model for Sanfilippo syndrome. However, the same mutation in an independently obtained mutant did not replicate these phenotypes, suggesting the existence of genetic modifiers in the strain used to generate the deletions. Naturally segregating epistatic partners that affect penetrance of the mutation can be identified by crossing the CG14291 deletion line to lines of the Drosophila melanogaster Genetic Reference Panel and screening for the observed phenotypes.