Mucopolysaccharidosis type IIIC or
Sanfilippo syndrome type C (
MPS IIIC, MIM #252930) is an autosomal recessive disorder caused by deficiency of the lysosomal membrane
enzyme,
heparan sulfate acetyl-CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT, EC 2.3.1.78), which catalyses transmembrane acetylation of the terminal
glucosamine residues of
heparan sulfate prior to their hydrolysis by
alpha-N-acetylglucosaminidase. Lysosomal storage of undegraded
heparan sulfate in the cells of affected patients leads to neuronal death causing neurodegeneration and is accompanied by mild visceral and skeletal abnormalities, including coarse
facies and joint stiffness. Surprisingly, the majority of
MPS IIIC patients carrying missense mutations are as severely affected as those with splicing errors, frame shifts or
nonsense mutations resulting in the complete absence of HGSNAT
protein.In order to understand the effects of the missense mutations in HGSNAT on its enzymatic activity and biogenesis, we have expressed 21
mutant proteins in cultured human fibroblasts and COS-7 cells and studied their folding, targeting and activity. We found that 17 of the 21 missense mutations in HGSNAT caused misfolding of the
enzyme, which is abnormally glycosylated and not targeted to the lysosome, but retained in the endoplasmic reticulum. The other 4 mutants represented rare polymorphisms which had no effect on the activity, processing and targeting of the
enzyme. Treatment of patient cells with a competitive HGSNAT inhibitor,
glucosamine, partially rescued several of the expressed mutants. Altogether our data provide an explanation for the severity of
MPS IIIC and suggest that search for
pharmaceutical chaperones can in the future result in therapeutic options for this disease.