HGSNAT – Mucopolysaccharidosis Type III

HGSNAT encodes heparan acetyl-CoA:alpha-glucosaminide N-acetyltransferase, a lysosomal membrane enzyme required for the transmembrane acetylation of heparan sulfate. Biallelic loss-of-function variants in HGSNAT cause autosomal recessive mucopolysaccharidosis type IIIC (Sanfilippo C syndrome), one of four subtypes of MPS III. Patients typically present in early childhood with developmental delay, progressive neurocognitive decline, hepatomegaly, ataxia, and seizures. Urinary glycosaminoglycan excretion is markedly elevated, and leukocyte HGSNAT activity is profoundly reduced (PMID:23301227). Genetic confirmation is achieved by sequencing, which reveals a spectrum of splice-site, nonsense, frameshift, and missense variants.

Autosomal recessive inheritance is supported by reports of over 78 probands from 22 unrelated families with confirmed HGSNAT variants (PMID:31228227). Segregation analysis in a large Colombian pedigree documented 11 affected relatives harboring the homozygous c.1360C>T (p.Gln454Ter) variant, consistent with founder-effect in an endogamous community (PMID:27733599). Case series in Korean, Tunisian, Italian, Spanish, and Chinese cohorts expand the allelic spectrum to at least 27 novel disease-causing variants, including deep-intronic and splice-site mutations (PMID:31228227). The recurrent c.234+1G>A and c.372-2A>G splice variants are observed across European and Moroccan patients and share a common haplotype, indicating ancient founder events.

Experimental studies demonstrate that missense mutations often result in protein misfolding, endoplasmic reticulum retention, loss of glycosylation, and absent lysosomal targeting. Heterologous expression of mutant HGSNAT in fibroblasts and COS-7 cells yields negligible enzyme activity for the majority of variants, whereas treatment with competitive inhibitors partially rescues folding defects (PMID:19823584). Knock-out mouse models recapitulate neurodegeneration and heparan sulfate storage, and lentiviral gene complementation restores enzymatic function in patient-derived cells. No reports to date have refuted HGSNAT’s role in MPS IIIC.

Integration of genetic and functional data establishes a definitive gene–disease relationship. The high burden of allelic heterogeneity, consistent segregation in pedigrees, and concordant biochemical assays exceed the maximum thresholds for ClinGen scoring, confirming a definitive classification. Clinically, HGSNAT genetic testing enables early molecular diagnosis, informs carrier screening in high-risk populations, and guides eligibility for emerging enzyme replacement or gene therapy trials. Key Take-home: Biallelic HGSNAT variants definitively underlie mucopolysaccharidosis type III, with robust genetic and functional corroboration supporting diagnostic and therapeutic strategies.

References

• Annals of laboratory medicine • 2013 • The first Korean case of mucopolysaccharidosis IIIC (Sanfilippo syndrome type C) confirmed by biochemical and molecular investigation PMID:23301227
• Human Mutation • 2007 • Mutational analysis of the HGSNAT gene in Italian patients with mucopolysaccharidosis IIIC (Sanfilippo C syndrome) PMID:17397050
• Human Mutation • 2019 • Molecular characterization of a large group of Mucopolysaccharidosis type IIIC patients reveals the evolutionary history of the disease PMID:31228227
• Journal of child neurology • 2017 • Natural History of Sanfilippo Syndrome Type C in Boyacá, Colombia PMID:27733599
• PLoS One • 2009 • Protein misfolding as an underlying molecular defect in mucopolysaccharidosis III type C PMID:19823584

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