The lysosomal degradative pathway of sulfated glycosaminoglycans (GAG) comprises a sophisticated hydrolytic network of highly specific glycosidases and sulfatases for complete degradation of these complex polysaccharides to sulfate and monosaccharides.
1–5 For each sulfate residue in different positions of the sugar moiety, distinct sulfatases are indispensable for their desulfation, which in turn is a prerequisite for glycosidic hydrolysis. Pathogenic mutations in genes coding for these hydrolytic enzymes lead to impaired degradation of GAGs and as a consequence to an accumulation of the corresponding substrates in lysosomes, a clinical situation described as lysosomal storage disorder (LSD). Disorders resulting from impaired lysosomal degradation of sulfated GAGs (heparan sulfate [HS], dermatan sulfate, chondroitin sulfate, and keratan sulfate) are summarized as mucopolysaccharidoses (MPSs).
1–6 One subgroup of the MPSs is Sanfilippo syndrome (MPS type III), which exclusively affects the degradation of HS. Mutations in genes coding for four different enzymes, needed for the removal of sulfated glucosamine residues of HS, are known to cause MPS III subtypes in humans, including N-sulfoglucosamine sulfohydrolase (encoded by
SGSH; MPS IIIA), N-α-acetylglucosaminidase (encoded by
NAGLU; MPS IIIB), heparan-α-glucosaminide N-acetyltransferase (encoded by
HGSNAT; MPS IIIC), and N-acetylglucosamine-6-sulfatase (encoded by
GNS; MPS IIID).
3,7 Taking all pathogenic mutations in these four genes together, MPS III is the most frequently occurring type of MPS with a reported prevalence in different populations of 0.28 to 4.1 per 100,000 births.
7 We have shown recently that a fifth enzyme is critical for complete degradation of HS glucosamine residues when sulfated in the C3 position of glucosamine: Arylsulfatase G (ARSG), also termed N-sulfoglucosamine-3-O-sulfatase.
6,8 We have generated
Arsg knockout (KO) mice, and have demonstrated accumulation of HS in different organ systems including liver, kidney, and brain.
6 Due to its assigned role in the degradation of HS and the resulting Sanfilippo syndrome-like pathological alterations, we tentatively assigned this MPS type as MPS IIIE. Compared to mouse models of the other MPS III subtypes,
9–11 Arsg KO mice presented with a milder phenotype and a later onset of the disease, with Purkinje cell degeneration in the cerebellum as the major neurological phenotype.
12 Severe ataxia and Purkinje cell degeneration also was observed in an American Staffordshire Terrier dog pedigree that lacks functional ARSG due to a point mutation in the
Arsg gene.
13 This canine model was assigned as a model of neuronal ceroid lipofuscinosis (NCL) because of the large amounts of accumulated lipofuscin in neurons. Human patients carrying pathogenic mutations in
ARSG have not been identified until now.