Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) (HGSNAT)

Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) is a critical lysosomal membrane enzyme involved in the catabolism of heparan sulfate (UniProt Q68CP4). It catalyzes the acetylation of terminal alpha-glucosamine residues, using acetyl-CoA from the cytosol as a donor (NCBI Gene 138050). This acetylation is a mandatory step that allows the subsequent action of alpha-N-acetylglucosaminidase in the degradation pathway. Deficiencies in HGSNAT lead to Mucopolysaccharidosis type IIIC (MPS IIIC), also known as Sanfilippo syndrome type C, a severe lysosomal storage disorder (OMIM 252930). Clinical manifestations of MPS IIIC include progressive neurodegeneration, intellectual disability, and behavioral disturbances (Feldhammer et al., 2009). Additionally, certain mutations in the HGSNAT gene have been linked to non-syndromic retinitis pigmentosa (Haer-Wigman et al., 2015). As an integral membrane protein, HGSNAT is not amenable to traditional enzyme replacement therapy, which typically targets soluble proteins (Canals et al., 2015). Current therapeutic research focuses on pharmacological chaperones, such as glucosamine, which aim to stabilize misfolded mutant enzymes (PubMed PMID: 31433069). Gene therapy approaches using viral vectors to deliver functional HGSNAT are also under investigation to address the central nervous system symptoms. Monitoring treatment efficacy involves measuring heparan sulfate levels in urine or cerebrospinal fluid and assessing enzymatic activity in patient cells.

Other names

Heparan sulfate acetyl-CoA:alpha-glucosaminide N-acetyltransferaseSanfilippo syndrome type C proteinAcetyl-CoA:alpha-glucosaminide N-acetyltransferaseTMEM76

Pharmacological chaperoning to stabilize misfolded enzyme variants and restore lysosomal activity; Gene replacement therapy to provide functional HGSNAT expression.