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GUSB
glucuronidase beta
The GUSB gene encodes the beta-glucuronidase enzyme, which is crucial for the breakdown of certain large sugar molecules within cellular compartments called lysosomes. The GUSB gene is responsible for producing the beta-glucuronidase enzyme.
GUSB is located on the long (q) arm of chromosome 7, at band 7q11.21. Arm ratio per GRCh38 - banding schematic.
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Overview
The GUSB gene provides instructions for making an enzyme known as beta-glucuronidase. This enzyme is primarily located in lysosomes, which are cellular organelles responsible for breaking down and recycling various types of molecules. Beta-glucuronidase is essential for the normal catabolism of glycosaminoglycans (GAGs), complex sugar chains that are important components of connective tissues. Without functional beta-glucuronidase, GAGs can accumulate in cells, leading to a condition called mucopolysaccharidosis type VII (MPS VII).
What the gene does
The primary function of the GUSB gene product, beta-glucuronidase, is to break down specific glycosaminoglycans (GAGs) within lysosomes. GAGs are long chains of sugar molecules, including dermatan sulfate, heparan sulfate, and chondroitin sulfate. Beta-glucuronidase acts by removing glucuronic acid, a specific sugar, from one end of these GAG chains, thereby facilitating their degradation. This stepwise breakdown is critical for maintaining cellular health and preventing the accumulation of these large molecules. When the beta-glucuronidase enzyme is deficient or non-functional due to GUSB variants, GAGs cannot be properly processed and instead build up inside cells, disrupting normal cellular processes.
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Chromosome location
The GUSB gene is situated on chromosome 7. Specifically, its location is assigned to the long arm of chromosome 7 at position 11.21, denoted as 7q11.21. This genomic address specifies the precise region where the GUSB gene can be found within the human genome.
Protein structure
The GUSB gene encodes a protein that is 651 amino acids long. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the GUSB gene can alter the function or production of the beta-glucuronidase enzyme. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions within the gene sequence. Many identified variants lead to a reduction or complete loss of enzyme activity, which impairs the cellular ability to break down specific glycosaminoglycans.
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.1145G>A | p.Arg382His | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis type 7 |
c.1455dup | p.Asn486Ter | Pathogenic | ★★☆☆ | Mucopolysaccharidosis type 7 |
c.1476_1476+13del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis type 7 |
c.1832G>A | p.Arg611Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis type 7 |
c.499C>T | p.Arg167Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis type 7 |
c.507dup | p.Ile170fs | Pathogenic | ★★☆☆ | Mucopolysaccharidosis type 7 |
c.581+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | GUSB-related disorder |
c.724+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis type 7 |
c.738C>G | p.Tyr246Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis type 7 |
c.91C>T | p.Gln31Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Mucopolysaccharidosis type 7 |
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 GUSB gene are known to cause mucopolysaccharidosis type VII (MPS VII), also referred to as Sly syndrome. This is an inherited lysosomal storage disorder characterised by the accumulation of glycosaminoglycans in various tissues and organs. The severity and specific symptoms of MPS VII can vary widely among affected individuals.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic GUSB 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 GUSB gene is included in several NHS England Genomic Medicine Service national test directories, indicating its clinical relevance in the UK. It is listed as 'green' on PanelApp for conditions such as Foetal anomalies, Foetal hydrops, Hydrocephalus, Intellectual disability, Lysosomal storage disorder, Mucopolysaccharideosis, Gaucher, Fabry, and Skeletal dysplasia, among others. A 'green' rating signifies that there is sufficient evidence for the gene to be considered causally associated with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the GUSB gene?
The GUSB gene provides instructions for creating an enzyme called beta-glucuronidase. This enzyme is crucial for breaking down specific large sugar molecules, known as glycosaminoglycans (GAGs), within the cell's recycling centres, the lysosomes.
What happens if the GUSB gene doesn't work correctly?
If the GUSB gene has pathogenic variants, the beta-glucuronidase enzyme may not function properly or may be entirely absent. This leads to the accumulation of GAGs inside cells, which can cause a rare genetic condition called mucopolysaccharidosis type VII (MPS VII).
How is mucopolysaccharidosis type VII (MPS VII) inherited?
Mucopolysaccharidosis type VII (MPS VII), caused by pathogenic variants in the GUSB gene, is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the pathogenic variant, one from each parent, to develop the condition. People with only one pathogenic variant copy are typically carriers and do not show symptoms.
References
- Tomatsu S, Montaño AM, Dung VC. Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome). Human mutation. 2009. PMID: 19224584
- Storch S, Wittenstein B, Islam R. Mutational analysis in longest known survivor of mucopolysaccharidosis type VII. Human genetics. 2003. PMID: 12522561
- Vervoort R, Islam MR, Sly WS. Molecular analysis of patients with beta-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII. American journal of human genetics. 1996. PMID: 8644704