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GANAB
glucosidase II alpha subunit
The *GANAB* gene provides instructions for making the alpha subunit of glucosidase II, an enzyme crucial for the correct folding and quality control of newly synthesised proteins. The *GANAB* gene encodes a component of the glucosidase II enzyme, which plays a vital role in the endoplasmic reticulum's protein quality control system.
GANAB is located on the long (q) arm of chromosome 11, at band 11q12.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The *GANAB* gene, also known as glucosidase II alpha subunit, is integral to the proper functioning of cells, particularly in the process of protein maturation. It provides the genetic blueprint for one of the two subunits of the glucosidase II enzyme. This enzyme is primarily active within the endoplasmic reticulum (ER), a cellular organelle responsible for synthesising and folding proteins.
The activity of glucosidase II, guided by the *GANAB* gene, is essential for ensuring that newly made proteins achieve their correct three-dimensional structure before being transported to their final destinations within the cell or secreted outside it. Defects in this process due to *GANAB* variants can lead to an accumulation of misfolded proteins, potentially impacting cellular health and organ function, particularly in the kidneys and liver.
What the gene does
The *GANAB* gene codes for the alpha subunit of glucosidase II, an enzyme that belongs to the glycosyl hydrolase family. Glucosidase II functions within the endoplasmic reticulum (ER), a cellular compartment where proteins are synthesised, folded, and modified. Its primary role is to act as an N-glycan processing enzyme, specifically removing glucose residues from N-linked glycans attached to newly formed proteins.
This glucose trimming is a crucial step in the calnexin/calreticulin cycle, which is a protein quality control pathway. Through this cycle, glucosidase II facilitates the chaperone-assisted folding of glycoproteins. By removing specific glucose residues, it allows proteins to re-enter the folding cycle until they achieve their native, stable conformation. If a protein fails to fold correctly after several attempts, the glucosidase II pathway, in conjunction with other ER quality control mechanisms, helps to target these misfolded proteins for degradation rather than allowing their accumulation.
Therefore, the *GANAB* gene product is central to maintaining the healthy protein landscape within the ER, preventing the build-up of potentially toxic misfolded proteins, and ensuring that only correctly folded and functional proteins are released from the ER. This quality control is vital for the normal physiological function of various tissues and organs, including the kidneys and liver.
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Chromosome location
The *GANAB* gene is situated on chromosome 11, specifically at position 11q12.3. Chromosome 11 is one of the 23 pairs of chromosomes in humans, containing a significant portion of the human genome. The 'q' in 11q12.3 indicates that the gene is located on the long arm of chromosome 11, while '12.3' refers to a specific band within that region. This precise genomic address helps in mapping the location of genes and understanding their inheritance patterns. The gene spans approximately 18 kilobases of DNA.
Protein structure
The *GANAB* gene provides instructions for a protein with a length of 944 amino acids, which forms the alpha subunit of glucosidase II. Within this protein, a notable feature is a Disordered region located between amino acids 181 and 238. Disordered regions are segments of proteins that do not adopt a stable three-dimensional structure under physiological conditions. Despite their lack of fixed structure, these regions often play critical roles in protein function, including molecular recognition, signalling, and serving as flexible linkers. In the context of glucosidase II alpha subunit, this region may contribute to its interactions with other proteins or its substrate, allowing for conformational flexibility necessary for its enzymatic activity in protein quality control.
Key variants
Variants within the *GANAB* gene can alter the function of the glucosidase II alpha subunit, potentially leading to the misfolding or impaired processing of other cellular proteins. Some variants may cause the protein to be non-functional, while others might lead to subtle changes that disrupt its enzymatic activity or its interaction with the protein quality control machinery. These genetic changes can be inherited in an autosomal recessive or autosomal dominant manner, influencing the risk and presentation of associated conditions. The impact of a specific *GANAB* variant can depend on its location within the gene and the nature of the amino acid change it causes.
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.1240C>T | p.Gln414Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Polycystic kidney disease 3 with or without polycystic liver disease |
c.152_153del | p.Arg51fs | Pathogenic/Likely pathogenic | ★★☆☆ | Polycystic kidney disease 3 with or without polycystic liver disease |
c.181C>T | p.Arg61Ter | Pathogenic | ★★☆☆ | not provided |
c.1848_1849del | p.Asp618fs | Pathogenic | ★★☆☆ | Polycystic kidney disease 3 with or without polycystic liver disease |
c.199_200del | p.Leu67fs | Pathogenic/Likely pathogenic | ★★☆☆ | Polycystic kidney disease 3 with or without polycystic liver disease |
c.2434C>T | p.Arg812Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Polycystic kidney disease 3 with or without polycystic liver disease |
c.2443C>T | p.Arg815Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Polycystic kidney disease 3 with or without polycystic liver disease |
c.490C>T | p.Arg164Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Polycystic kidney disease 3 with or without polycystic liver disease |
c.516_517delinsAT | p.Arg173Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Polycystic kidney disease 3 with or without polycystic liver disease |
c.1495G>T | p.Glu499Ter | Pathogenic | ★☆☆☆ | Polycystic kidney disease 3 with or without polycystic liver disease |
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 *GANAB* gene are associated with various forms of kidney and liver disease, primarily those characterised by the development of cysts. These conditions include different types of cystic kidney disease and polycystic liver disease. The disruption of the protein quality control system due to *GANAB* variants can lead to cellular dysfunction in these organs, contributing to cyst formation and progressive organ damage.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic GANAB variants typically follow ar/ad 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
Within the UK, the *GANAB* gene is recognised on several NHS Genomic Medicine Service national test directories, specifically within gene panels related to kidney and liver conditions. It holds a 'green' status for Cystic kidney disease, Ductal plate malformation, Polycystic liver disease (R173), and Foetal anomalies (R21). A 'green' status indicates that there is sufficient evidence that this gene is associated with the specified condition, and testing for variants in *GANAB* is recommended as part of the accredited diagnostic pathways for these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
General lifestyle approaches that support kidney and liver health may be beneficial for individuals with *GANAB* gene variants, although specific interventions for *GANAB*-related conditions are still being researched. Maintaining a balanced diet, rich in fruits, vegetables, and whole grains, combined with regular physical activity, generally supports overall organ function. Limiting the intake of processed foods, excessive salt, and sugar can contribute to better kidney and liver health in the general population. Reducing alcohol consumption is also widely recommended to protect liver function. However, specific dietary or lifestyle recommendations should always be discussed with a healthcare professional.
Supplement considerations
There is currently no conclusive evidence to suggest that specific dietary supplements can prevent, treat, or mitigate the effects of conditions associated with *GANAB* gene variants. While some supplements are marketed for kidney or liver health, their efficacy and safety in individuals with specific genetic conditions like those linked to *GANAB* are not well-established. Individuals considering supplements should consult with a healthcare provider to discuss potential benefits versus risks, as some supplements can interact with medications or have adverse effects, especially in the context of compromised organ function.
Frequently asked questions
What does the *GANAB* gene do?
The *GANAB* gene provides instructions for making the alpha subunit of glucosidase II, an enzyme vital for the proper folding and quality control of proteins within the endoplasmic reticulum.
Which conditions are associated with *GANAB* gene variants?
Variants in the *GANAB* gene are associated with various kidney and liver conditions, including cystic kidney disease and polycystic liver disease.
How are *GANAB* gene variants inherited?
Variants in the *GANAB* gene can be inherited in either an autosomal recessive or autosomal dominant pattern, meaning one or two altered copies of the gene can lead to a condition.
Is *GANAB* testing available in the UK?
Yes, *GANAB* is part of several NHS Genomic Medicine Service national test directories for conditions like cystic kidney disease and polycystic liver disease.
Can lifestyle changes prevent *GANAB*-related conditions?
While general healthy lifestyle practices support organ health, there is no specific evidence that they can prevent or cure *GANAB*-related genetic conditions. Always consult a healthcare professional for personalised advice.