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AGL
amylo-alpha-1,6-glucosidase and 4-alpha-glucanotransferase
The AGL gene encodes an enzyme essential for breaking down glycogen, the body's stored form of glucose, playing a critical role in energy metabolism. The AGL gene provides instructions for producing the glycogen debranching enzyme.
AGL is located on the short (p) arm of chromosome 1, at band 1p21.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The AGL gene, fully known as amylo-alpha-1,6-glucosidase and 4-alpha-glucanotransferase, is crucial for normal energy metabolism. It provides the genetic blueprint for an enzyme responsible for breaking down glycogen, a stored form of glucose. This breakdown releases glucose, which cells use for energy.
Disruptions in the AGL gene's function can impair the body's ability to properly metabolise glycogen, leading to its accumulation in various tissues. Such accumulation can result in specific inherited metabolic disorders, impacting organs such as the liver and muscles.
What the gene does
The AGL gene directs the synthesis of the glycogen debranching enzyme, which has a dual enzymatic function: amylo-alpha-1,6-glucosidase and 4-alpha-glucanotransferase activities. Glycogen is a highly branched polysaccharide, a complex carbohydrate made of many glucose units.
The enzyme plays a key role in dismantling these branched glycogen structures. Specifically, it removes the glucose molecules that form the branching points in glycogen, making the remaining linear chains accessible for further breakdown by other enzymes. This sequential process ensures that stored glycogen can be efficiently converted back into glucose to meet the body's energy demands. The AGL gene produces different versions (isoforms) of this enzyme, which vary in size and are active in different tissues, reflecting the diverse metabolic needs across the body.
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Chromosome location
The AGL gene is situated on the short arm of chromosome 1, specifically at position 1p21.2. This location refers to a particular band on the chromosome where the gene resides. The gene contains the instructions for making a protein composed of 1532 amino acids.
Protein structure
The AGL gene encodes a protein that is 1532 amino acids long. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variations in the AGL gene can alter the function or production of the glycogen debranching enzyme. These changes can range from small alterations in the DNA sequence to larger structural rearrangements. Many identified variants lead to a premature stop signal in the genetic instructions, resulting in a nonfunctional enzyme that cannot properly break down glycogen.
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.1107del | p.Glu369fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease type III |
c.1177C>T | p.Gln393Ter | Pathogenic | ★★☆☆ | AGL-related disorder |
c.1183C>T | p.Gln395Ter | Pathogenic | ★★☆☆ | Glycogen storage disease type III |
c.1777del | p.Val593fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease type III |
c.1999C>T | p.Gln667Ter | Pathogenic | ★★☆☆ | Glycogen storage disease type III |
c.2214del | p.Ser738fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease type III |
c.3971_3972del | p.Ser1323_Tyr1324insTer | Pathogenic | ★★☆☆ | Glycogen storage disease type III |
c.440_441del | p.Leu147fs | Pathogenic | ★★☆☆ | Glycogen storage disease type III |
c.594del | p.Gln199fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease type III |
c.808G>T | p.Gly270Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease type III |
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 AGL gene are primarily associated with Glycogen Storage Disease Type III, also known as Debrancher deficiency (GSD IIIa). This condition is inherited in an autosomal recessive manner, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to develop the condition. GSD III leads to an abnormal accumulation of glycogen in the liver, muscles, and sometimes the heart, due to the impaired ability to debranch and fully break down glycogen.
- Debrancher deficiency (GSD IIIa)
- Glycogen storage disease type III Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic AGL 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 AGL gene is recognised within several NHS Genomic Medicine Service (GMS) pathways in the UK. It is categorised as a 'green' gene on PanelApp for conditions such as Glycogen storage disease (R274), Acute rhabdomyolysis (R419), and Foetal anomalies (R21). It is also listed on panels for Likely inborn error of metabolism (R98), Ketotic hypoglycaemia, Rhabdomyolysis and metabolic muscle disorders, Undiagnosed metabolic disorders, and DDG2P, indicating its established role in these clinical contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the AGL gene?
The AGL gene provides instructions for creating the glycogen debranching enzyme. This enzyme is crucial for breaking down glycogen, which is the body's stored form of glucose, into usable energy.
What condition is associated with variants in the AGL gene?
Variants in the AGL gene are primarily associated with Glycogen Storage Disease Type III (GSD III), also known as Debrancher deficiency. This condition results from the body's inability to properly break down branched glycogen.
How is Glycogen Storage Disease Type III inherited?
Glycogen Storage Disease Type III is inherited in an autosomal recessive manner. This means that an individual must inherit two altered copies of the AGL gene, one from each parent, to develop the condition.
References
- Cheng A, Zhang M, Okubo M. Distinct mutations in the glycogen debranching enzyme found in glycogen storage disease type III lead to impairment in diverse cellular functions. Human molecular genetics. 2009. PMID: 19299494
- Lucchiari S, Pagliarani S, Salani S. Hepatic and neuromuscular forms of glycogenosis type III: nine mutations in AGL. Human mutation. 2006. PMID: 16705713
- Endo Y, Horinishi A, Vorgerd M. Molecular analysis of the AGL gene: heterogeneity of mutations in patients with glycogen storage disease type III from Germany, Canada, Afghanistan, Iran, and Turkey. Journal of human genetics. 2006. PMID: 17047887
- Frisbie JH, O'Connell DJ, Tow DE. Autologous radioiodinated fibrinogen, simplified. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 1975. PMID: 1194993