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GYS2
glycogen synthase 2
The GYS2 gene provides instructions for making liver glycogen synthase, an enzyme crucial for producing glycogen in the liver, which serves as a vital energy reserve. The GYS2 gene is responsible for encoding liver glycogen synthase, an enzyme found exclusively in liver cells.
GYS2 is located on the short (p) arm of chromosome 12, at band 12p12.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The GYS2 gene, or glycogen synthase 2, plays a fundamental role in human metabolism. It provides the genetic blueprint for producing an enzyme known as liver glycogen synthase. This enzyme is solely expressed in liver cells, where its primary function is to convert excess glucose into glycogen, a complex sugar that acts as the body's main stored form of energy. Maintaining adequate liver glycogen stores is essential for regulating blood glucose levels, particularly during periods between meals when dietary glucose is not readily available.
Inherited conditions associated with variations in the GYS2 gene are typically passed down in an autosomal recessive manner, meaning an individual must inherit two altered copies of the gene (one from each parent) to be affected. Understanding the GYS2 gene's function and associated conditions is important for diagnosing and managing related metabolic disorders.
What the gene does
The GYS2 gene directs the synthesis of liver glycogen synthase, an enzyme critical for glucose homeostasis. Within liver cells, this enzyme is responsible for linking together molecules of simple sugar glucose to form glycogen. Glycogen serves as the body's primary energy storage molecule, analogous to starch in plants. When glucose is consumed through food, the liver takes up a portion of it and, with the help of liver glycogen synthase, converts it into glycogen for storage. This stored glycogen acts as a readily available energy reserve. When the body requires glucose to maintain normal blood sugar levels, especially between meals or during fasting, the liver can rapidly break down its glycogen stores to release glucose back into the bloodstream. This process is crucial for providing energy to the brain and other tissues that depend on glucose as their main fuel source. Dysfunction in the GYS2 enzyme can impair the liver's ability to store glycogen, leading to disruptions in blood glucose regulation.
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Chromosome location
The GYS2 gene is located on chromosome 12, specifically at position 12p12.1. This genomic address specifies the precise location of the gene within the human genome. The gene spans a segment of DNA on the short (p) arm of chromosome 12, indicating its position relative to other genes and genetic markers.
Protein structure
The protein encoded by the GYS2 gene, liver glycogen synthase, consists of 703 amino acids. Its structure includes a significant Disordered region located between amino acids 628 and 703. While the overall domain architecture of liver glycogen synthase facilitates its enzymatic activity, this specific disordered region may play a role in protein-protein interactions or regulatory mechanisms within the cell.
Key variants
Variations within the GYS2 gene can impact the function of the liver glycogen synthase enzyme. These genetic changes can range from single base-pair substitutions to larger deletions or insertions, and their effect on protein function can vary. Some variants may lead to a complete loss of enzyme activity, while others might only partially impair it. The classification of these variants as pathogenic, likely pathogenic, or of uncertain significance helps to understand their potential clinical impact.
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.1062+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disorder due to hepatic glycogen synthase deficiency |
c.1081del | p.Thr361fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease |
c.1156C>T | p.Arg386Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disorder due to hepatic glycogen synthase deficiency |
c.1423-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | GYS2-related disorders |
c.1557_1579del | p.Thr520fs | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disorder due to hepatic glycogen synthase deficiency |
c.176G>A | p.Trp59Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disease |
c.457del | p.Met152_Leu153insTer | Pathogenic | ★★☆☆ | Glycogen storage disorder due to hepatic glycogen synthase deficiency |
c.465del | p.Phe155fs | Pathogenic | ★★☆☆ | Glycogen storage disorder due to hepatic glycogen synthase deficiency |
c.495+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Glycogen storage disorder due to hepatic glycogen synthase deficiency |
c.547C>T | p.Gln183Ter | Pathogenic | ★★☆☆ | Glycogen storage disorder due to hepatic glycogen synthase deficiency |
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 variations in the GYS2 gene are primarily associated with a form of glycogen storage disease type 0, specifically affecting the liver. This condition arises when the liver glycogen synthase enzyme is non-functional or absent, leading to a severe deficiency or complete lack of glycogen storage in liver cells. Consequently, individuals with this condition may experience challenges in maintaining stable blood glucose levels, particularly during fasting, as the liver cannot adequately release stored glucose into the bloodstream.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic GYS2 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
In the UK, the GYS2 gene is recognised on several NHS Genomic Medicine Service national panels via PanelApp. It is listed on panels for Glycogen storage disease, Ketotic hypoglycaemia, Likely inborn error of metabolism, and Undiagnosed metabolic disorders, all categorised with a 'green' status, indicating strong evidence for gene-disease association in a clinical diagnostic setting.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the GYS2 gene?
The GYS2 gene provides instructions for making liver glycogen synthase, an enzyme crucial for converting glucose into glycogen in the liver. This stored glycogen acts as the body's main energy reserve, helping to maintain stable blood glucose levels.
How is glycogen storage disease type 0 related to GYS2?
Glycogen storage disease type 0 affecting the liver is caused by pathogenic variations in the GYS2 gene. These variations result in a non-functional or absent liver glycogen synthase enzyme, preventing the liver from properly storing glycogen.
What is the inheritance pattern for conditions linked to GYS2?
Conditions associated with variations in the GYS2 gene, such as liver glycogen storage disease type 0, typically follow an autosomal recessive inheritance pattern. This means an individual must inherit two altered copies of the gene, one from each parent, to develop the condition.
References
- Soggia AP, Correa-Giannella ML, Fortes MA. A novel mutation in the glycogen synthase 2 gene in a child with glycogen storage disease type 0. BMC medical genetics. 2010. PMID: 20051115
- Weinstein DA, Correia CE, Saunders AC. Hepatic glycogen synthase deficiency: an infrequently recognized cause of ketotic hypoglycemia. Molecular genetics and metabolism. 2006. PMID: 16337419
- Bachrach BE, Weinstein DA, Orho-Melander M. Glycogen synthase deficiency (glycogen storage disease type 0) presenting with hyperglycemia and glucosuria: report of three new mutations. The Journal of pediatrics. 2002. PMID: 12072888
- Orho M, Bosshard NU, Buist NR. Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0. The Journal of clinical investigation. 1998. PMID: 9691087