On this page
GCK
glucokinase
The GCK gene provides instructions for producing glucokinase, an enzyme vital for glucose metabolism and the regulation of insulin secretion, with implications for various forms of diabetes. Glucokinase, encoded by the GCK gene, acts as a glucose sensor in the body, primarily in the pancreas and liver.
GCK is located on the short (p) arm of chromosome 7, at band 7p13. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 7 in the library →Overview
The GCK gene provides the genetic blueprint for glucokinase, an enzyme fundamental to the body's glucose metabolism. This protein functions as a crucial glucose sensor, particularly in pancreatic beta cells and the liver, initiating responses that help manage blood sugar levels. Understanding the GCK gene is important for its role in conditions characterised by abnormal glucose regulation.
What the gene does
Glucokinase, the protein produced from the GCK gene, plays a central role in the initial steps of glucose metabolism within cells. In pancreatic beta cells, it acts as a glucose sensor, detecting rising blood glucose concentrations and subsequently stimulating the release of insulin, a hormone that facilitates glucose uptake by cells. In the liver, glucokinase is involved in regulating the conversion of excess glucose into glycogen for storage. This enzyme's activity directly influences how the body processes sugars and maintains glucose homeostasis, ensuring a balanced energy supply. Its function is critical for both short-term blood sugar control and long-term energy storage.
Video: Genetics 101
Chromosome location
The GCK gene is situated on chromosome 7, specifically at position 7p13. This genomic location indicates where the gene resides within the human genome and contributes to its inherited characteristics.
Protein structure
The glucokinase protein consists of 465 amino acids. It features a prominent Hexokinase domain spanning amino acids 10-454. Within this larger domain, two key regions are identified: the Hexokinase small subdomain (amino acids 67-203) and the Hexokinase large subdomain (amino acids 204-443). These subdomains are integral to the enzyme's catalytic activity and glucose binding.
Key variants
Variants within the GCK gene can lead to changes in the glucokinase protein, potentially affecting its ability to process glucose and regulate insulin. These genetic alterations can impact glucose metabolism in various ways, ranging from subtle modifications in blood sugar levels to more significant health conditions. The specific effect of a variant often depends on its location and the nature of the change it introduces to the protein.
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 |
|---|---|---|---|---|
g.44189510C>G | - | Pathogenic | ★★★☆ | GCK-related disorder |
c.1010A>C | p.Gln337Pro | Pathogenic | ★★★☆ | Monogenic diabetes |
c.1016A>G | p.Glu339Gly | Pathogenic | ★★★☆ | Monogenic diabetes |
c.1019+1G>A | - | Pathogenic | ★★★☆ | Monogenic diabetes |
c.1019+1G>T | - | Pathogenic | ★★★☆ | Monogenic diabetes |
c.1019+2T>G | - | Pathogenic | ★★★☆ | Permanent neonatal diabetes mellitus |
c.1019G>A | p.Ser340Asn | Pathogenic | ★★★☆ | not provided |
c.1019G>C | p.Ser340Thr | Pathogenic | ★★★☆ | Maturity-onset diabetes of the young |
c.1020-1G>A | - | Pathogenic | ★★★☆ | not provided |
c.1020-1G>C | - | Pathogenic | ★★★☆ | Maturity-onset diabetes of the young type 2 |
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 GCK gene are associated with several conditions affecting glucose metabolism. One notable condition is MODY2 (GCK diabetes), a form of monogenic diabetes characterised by persistently elevated but generally mild fasting blood glucose levels. Other related conditions can include congenital hyperinsulinism, where too much insulin is produced, and certain types of neonatal diabetes, which can appear shortly after birth.
Inheritance pattern
Conditions caused by pathogenic GCK variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The GCK gene is included in several NHS England Genomic Medicine Service approved panels, indicating its clinical significance within the UK. It is assessed on panels for Congenital hyperinsulinism, Diabetes with additional phenotypes suggestive of a monogenic aetiology, Familial diabetes, Glucokinase-related fasting hyperglycaemia, Monogenic diabetes, and Neonatal diabetes, all of which are categorised as 'green' in PanelApp, signifying high evidence for their clinical utility.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the GCK gene do?
The GCK gene provides instructions for making glucokinase, an enzyme that acts as a glucose sensor in the body. It helps regulate blood sugar levels by prompting insulin release from the pancreas and by controlling glucose storage in the liver.
What is MODY2?
MODY2, also known as GCK diabetes, is a type of monogenic diabetes caused by variants in the GCK gene. It typically results in mildly elevated blood glucose levels from birth, often without severe symptoms, and usually develops before the age of 30.
How is the GCK gene relevant to diabetes?
The GCK gene is crucial for diabetes as its product, glucokinase, is central to glucose sensing and insulin secretion. Variants in this gene can impair these functions, leading to various forms of diabetes, including MODY2 and some cases of neonatal diabetes.
References
- Negahdar M, Aukrust I, Molnes J. GCK-MODY diabetes as a protein misfolding disease: the mutation R275C promotes protein misfolding, self-association and cellular degradation. Molecular and cellular endocrinology. 2014. PMID: 24001579
- Steele AM, Shields BM, Wensley KJ. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA. 2014. PMID: 24430320
- Osbak KK, Colclough K, Saint-Martin C. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Human mutation. 2009. PMID: 19790256
- Froguel P, Zouali H, Vionnet N. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. The New England journal of medicine. 1993. PMID: 8433729