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SGSH
N-sulfoglucosamine sulfohydrolase
The SGSH gene provides instructions for producing the sulfamidase enzyme, which is vital for the proper breakdown of complex sugar molecules called glycosaminoglycans within cells. The SGSH gene is responsible for creating an enzyme named sulfamidase, found in cellular compartments called lysosomes.
SGSH is located on the long (q) arm of chromosome 17, at band 17q25.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The SGSH gene encodes an enzyme known as N-sulfoglucosamine sulfohydrolase, more commonly referred to as sulfamidase. This enzyme is essential for the lysosomal degradation pathway, specifically targeting certain complex carbohydrates. Defects in the SGSH gene are associated with an inherited metabolic disorder known as Mucopolysaccharidosis type III, also called Sanfilippo syndrome.
What the gene does
The SGSH gene produces sulfamidase, an enzyme primarily located in lysosomes, which are cellular organelles responsible for waste breakdown and recycling. Sulfamidase plays a critical role in the catabolism of glycosaminoglycans (GAGs), long chains of sugar molecules. Specifically, it is involved in breaking down heparan sulphate, a type of GAG, by removing a sulphate group from glucosamine sugars at the end of the chain. Without functional sulfamidase, heparan sulphate accumulates within the lysosomes, leading to cellular dysfunction and the characteristic symptoms of Mucopolysaccharidosis type III.
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Chromosome location
The SGSH gene is situated on chromosome 17, specifically at position 17q25.3. This means it is located on the long (q) arm of chromosome 17, in region 25, band 3. The precise location helps in genetic mapping and understanding its genomic context.
Protein structure
The SGSH gene encodes a protein that is 502 amino acids in length. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the SGSH gene can alter the production or function of the sulfamidase enzyme. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions. Pathogenic variants typically lead to a reduction or complete loss of enzyme activity, impairing the body's ability to process specific complex sugars.
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.1069dup | p.Leu357fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-A |
c.120C>G | p.Tyr40Ter | Pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-A |
c.1317C>A | p.Tyr439Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-A |
c.1345C>T | p.Gln449Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-A |
c.250-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-A |
c.277C>T | p.Gln93Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-A |
c.48del | p.Leu17fs | Pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-A |
c.496C>T | p.Gln166Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-A |
c.691_698del | p.Ala231fs | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-A |
c.949+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis, MPS-III-A |
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 SGSH gene are known to cause Mucopolysaccharidosis type III (Sanfilippo syndrome), an inherited metabolic condition. This condition is inherited in an autosomal recessive manner, meaning an individual must inherit two altered copies of the gene (one from each parent) to be affected. The lack of functional sulfamidase leads to the accumulation of heparan sulphate in lysosomes, particularly affecting the central nervous system.
Inheritance pattern
Conditions caused by pathogenic SGSH 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 SGSH gene is included on several NHS Genomic Medicine Service national panels, indicating its clinical significance within the UK. It is assessed under categories such as DDG2P, Early onset or syndromic epilepsy, Intellectual disability, Likely inborn error of metabolism, Lysosomal storage disorder, Mucopolysaccharideosis, Gaucher, Fabry, Mucopolysaccharidosis type IIIA, Retinal disorders, Skeletal dysplasia, and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the role of the SGSH gene?
The SGSH gene provides instructions for making the sulfamidase enzyme. This enzyme is crucial for breaking down heparan sulphate, a type of complex sugar molecule, within lysosomes inside cells.
What condition is associated with SGSH gene variants?
Pathogenic variants in the SGSH gene are associated with Mucopolysaccharidosis type III, also known as Sanfilippo syndrome. This is a lysosomal storage disorder where heparan sulphate accumulates in cells.
How is Mucopolysaccharidosis type III inherited?
Mucopolysaccharidosis type III is inherited in an autosomal recessive manner. This means an individual must inherit two copies of the altered SGSH gene, one from each parent, to develop the condition.
References
- Valstar MJ, Ruijter GJ, van Diggelen OP. Sanfilippo syndrome: a mini-review. Journal of inherited metabolic disease. 2008. PMID: 18392742
- Meyer A, Kossow K, Gal A. The mutation p.Ser298Pro in the sulphamidase gene (SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis type IIIA (Sanfilippo A syndrome). Human mutation. 2008. PMID: 18407553
- Muschol N, Storch S, Ballhausen D. Transport, enzymatic activity, and stability of mutant sulfamidase (SGSH) identified in patients with mucopolysaccharidosis type III A. Human mutation. 2004. PMID: 15146460