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HGSNAT
heparan-alpha-glucosaminide N-acetyltransferase
The HGSNAT gene provides instructions for an enzyme called heparan-alpha-glucosaminide N-acetyltransferase, which plays a crucial role in the breakdown of specific molecules within cellular lysosomes. HGSNAT encodes an enzyme essential for the stepwise degradation of heparan sulphate, a type of glycosaminoglycan.
HGSNAT is located on the short (p) arm of chromosome 8, at band 8p11.21-p11.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The HGSNAT gene directs the production of an enzyme known as heparan-alpha-glucosaminide N-acetyltransferase. This enzyme is located within cellular compartments called lysosomes, which are responsible for the recycling and breakdown of various cellular components. Its primary function involves the degradation of complex sugar molecules, specifically heparan sulphate, as part of a larger metabolic pathway.
What the gene does
The HGSNAT enzyme, also known as N-acetyltransferase, functions within lysosomes to facilitate the breakdown of glycosaminoglycans (GAGs), particularly heparan sulphate. GAGs are long chains of sugar molecules, and their degradation occurs in a step-by-step manner. N-acetyltransferase specifically adds an acetyl group to the glucosamine sugar unit within heparan sulphate. This acetylation step is critical as it prepares the heparan sulphate molecule for subsequent stages in the degradation pathway. Without proper N-acetyltransferase activity, the breakdown of heparan sulphate is impaired, leading to its accumulation within cells.
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Chromosome location
The HGSNAT gene is situated on the short arm of chromosome 8, specifically at chromosomal band 8p11.21-p11.1. This region specifies the gene's precise address within the human genome.
Protein structure
The HGSNAT protein consists of 663 amino acids. It contains a Disordered region spanning amino acids 1-24. Additionally, a Lysosomal targeting region is found between amino acids 624-635, which is important for directing the enzyme to its correct cellular location within the lysosome.
Key variants
Variants within the HGSNAT gene can alter the function or production of the heparan-alpha-glucosaminide N-acetyltransferase enzyme. These changes can reduce or eliminate the enzyme's activity, leading to an inability to properly break down specific molecules. The spectrum of variants includes various types, many of which can affect single DNA building blocks.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1271G>T | p.Gly424Val | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 73 |
c.1323C>A | p.Tyr441Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-C |
c.1543-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-C |
c.1726+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-C |
c.416dup | p.Asn141fs | Pathogenic/Likely pathogenic | ★★☆☆ | HGSNAT-related disorder |
c.451del | p.Cys151fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-C |
c.494-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-C |
c.494-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 73 |
c.505dup | p.Ala169fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-C |
c.610G>T | p.Glu204Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-C |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the HGSNAT gene are known to cause Mucopolysaccharidosis type III (Sanfilippo), specifically type IIIC. This condition arises due to the impaired breakdown of heparan sulphate, which then accumulates within lysosomes. This accumulation can lead to a range of symptoms affecting various organ systems.
Inheritance pattern
Conditions caused by pathogenic HGSNAT variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The HGSNAT gene is recognised in the UK's NHS Genomic Medicine Service through its inclusion in several NHS Genomic Test Directory panels. It is categorised as 'green' for panels related to Intellectual disability, Likely inborn error of metabolism (R98), Lysosomal storage disorder (R276), Mucopolysaccharideosis, Gaucher, Fabry, Retinal disorders (R32), Skeletal dysplasia (R104), and Undiagnosed metabolic disorders, indicating its established role in these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the HGSNAT gene do?
The HGSNAT gene provides instructions for making an enzyme called heparan-alpha-glucosaminide N-acetyltransferase. This enzyme is crucial for breaking down heparan sulphate within lysosomes, which are the recycling centres of cells.
What happens if the HGSNAT gene doesn't work correctly?
If the HGSNAT gene doesn't function properly, the enzyme it produces will have reduced or absent activity. This leads to an accumulation of heparan sulphate within cells, primarily causing a condition called Mucopolysaccharidosis type IIIC.
Is Mucopolysaccharidosis type III an inherited condition?
Yes, Mucopolysaccharidosis type III, including type IIIC caused by HGSNAT variants, is an inherited condition. It typically follows an autosomal recessive inheritance pattern, meaning an individual must inherit two copies of the altered gene (one from each parent) to develop the condition.
References
- Feldhammer M, Durand S, Mrázová L. Sanfilippo syndrome type C: mutation spectrum in the heparan sulfate acetyl-CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT) gene. Human mutation. 2009. PMID: 19479962
- Feldhammer M, Durand S, Pshezhetsky AV. Protein misfolding as an underlying molecular defect in mucopolysaccharidosis III type C. PloS one. 2009. PMID: 19823584
- Ruijter GJ, Valstar MJ, van de Kamp JM. Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands. Molecular genetics and metabolism. 2008. PMID: 18024218
- Valstar MJ, Ruijter GJ, van Diggelen OP. Sanfilippo syndrome: a mini-review. Journal of inherited metabolic disease. 2008. PMID: 18392742
- Fan X, Zhang H, Zhang S. Identification of the gene encoding the enzyme deficient in mucopolysaccharidosis IIIC (Sanfilippo disease type C). American journal of human genetics. 2006. PMID: 16960811
- Hrebícek M, Mrázová L, Seyrantepe V. Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome). American journal of human genetics. 2006. PMID: 17033958