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ABCC8
ATP binding cassette subfamily C member 8
The ABCC8 gene provides genetic instructions for a crucial part of ATP-sensitive potassium (KATP) channels, which are vital for regulating insulin release from pancreatic beta cells. ABCC8, also known as sulfonylurea receptor 1 (SUR1), plays a central role in controlling blood glucose levels by influencing insulin secretion.
ABCC8 is located on the short (p) arm of chromosome 11, at band 11p15.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The ABCC8 gene encodes a protein that forms a critical component of the ATP-sensitive potassium (KATP) channels. These channels are predominantly found in the beta cells of the pancreas, where they play a fundamental role in controlling the release of insulin. Proper functioning of these channels is essential for maintaining stable blood glucose levels.
Disruptions to the ABCC8 gene can lead to a spectrum of disorders affecting glucose metabolism, ranging from conditions of excessive insulin secretion, such as congenital hyperinsulinism, to forms of diabetes where insulin production is insufficient.
What the gene does
The ABCC8 gene directs the production of a subunit, specifically SUR1, which is part of the ATP-sensitive potassium (KATP) channels. These channels are embedded in the cell membranes of pancreatic beta cells. Each functional KATP channel is composed of eight subunits: four derived from the ABCC8 gene and four from the KCNJ11 gene. These channels act as sensors for the cell's energy status, specifically responding to changes in ATP levels.
When blood glucose levels rise, glucose enters beta cells and is metabolised, leading to an increase in ATP production. This rise in ATP causes the KATP channels to close, initiating a cascade of events that culminates in the release of insulin. Insulin then helps to lower blood glucose. Therefore, the ABCC8-encoded protein is pivotal in linking glucose metabolism to insulin secretion, thereby regulating blood sugar.
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Chromosome location
The ABCC8 gene is located on chromosome 11, specifically at band 11p15.1. This position signifies its precise address within the human genome.
Protein structure
The ABCC8 protein consists of 1581 amino acids and is characterised by several distinct functional domains. These include two ABC transmembrane type-1 domains located at amino acid positions 299-602 and 1012-1306, respectively. Additionally, there are two ABC transporter domains, one spanning amino acids 679-929 and another from 1344-1578. A disordered region is also identified between amino acids 935-987.
Key variants
Variants within the ABCC8 gene can significantly impact its function, leading to altered KATP channel activity. These genetic changes can range from single amino acid substitutions to larger deletions or insertions, and their specific effect can vary depending on the nature and location of the variant within the gene. Such variants are typically inherited in an autosomal recessive pattern.
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.1176+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hyperinsulinism |
c.1254_1284dup | p.Met429Ter | Pathogenic | ★★☆☆ | Hyperinsulinemic hypoglycemia, familial, 1 |
c.1290G>A | p.Trp430Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperinsulinemic hypoglycemia, familial, 1 |
c.1330C>T | p.Gln444Ter | Pathogenic | ★★☆☆ | Hyperinsulinemic hypoglycemia, familial, 1 |
c.1332G>T | p.Gln444His | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1333-1013A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperinsulinemic hypoglycemia, familial, 1 |
c.1347_1348del | p.Ile450fs | Pathogenic | ★★☆☆ | Hyperinsulinemic hypoglycemia, familial, 1 |
c.1473T>G | p.Tyr491Ter | Pathogenic | ★★☆☆ | Hereditary hyperinsulinism |
c.148+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperinsulinemic hypoglycemia, familial, 1 |
c.1501G>A | p.Glu501Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Hyperinsulinemic hypoglycemia, familial, 1 |
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
Variants in the ABCC8 gene are primarily associated with conditions affecting insulin regulation. These include Congenital hyperinsulinism (diffuse, KATP) and Congenital hyperinsulinism (focal), both characterised by excessive insulin secretion and recurrent low blood glucose levels. Additionally, ABCC8 variants can cause various forms of monogenic diabetes, such as permanent neonatal diabetes mellitus and transient neonatal diabetes mellitus, where insulin production is impaired.
- Congenital hyperinsulinism (diffuse, KATP)
- Congenital hyperinsulinism (focal) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ABCC8 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
ABCC8 is recognised in the UK National Health Service (NHS) Genomic Medicine Service. It is listed on several green R-panels in NHS England's National Genomic Test Directory, including Congenital hyperinsulinism (R144), Monogenic diabetes (R141), Neonatal diabetes (R143), and Neonatal diabetes - small panel (R143.1). The gene is also relevant for Diabetes with additional phenotypes suggestive of a monogenic aetiology, Familial diabetes, and Pulmonary arterial hypertension (R188).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the ABCC8 gene?
The ABCC8 gene provides instructions for making part of the ATP-sensitive potassium (KATP) channels in pancreatic beta cells. These channels are crucial for regulating the release of insulin, which in turn controls blood glucose levels.
What happens if there are variants in the ABCC8 gene?
Variants in the ABCC8 gene can lead to conditions such as congenital hyperinsulinism, characterised by too much insulin, or various forms of monogenic diabetes, where insulin production is insufficient. Both scenarios result from disrupted KATP channel function.
How is the ABCC8 gene involved in blood sugar regulation?
The protein made by ABCC8 senses changes in the cell's energy state within pancreatic beta cells. When blood glucose levels rise, the KATP channels, which include the ABCC8 protein, close to trigger insulin secretion, helping to lower blood sugar.
References
- Bennett K, James C, Hussain K. Pancreatic β-cell KATP channels: Hypoglycaemia and hyperglycaemia. Reviews in endocrine & metabolic disorders. 2010. PMID: 20878482
- Edghill EL, Flanagan SE, Ellard S. Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11. Reviews in endocrine & metabolic disorders. 2010. PMID: 20922570
- Flanagan SE, Clauin S, Bellanné-Chantelot C. Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Human mutation. 2009. PMID: 18767144
- Sandal T, Laborie LB, Brusgaard K. The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy. Clinical genetics. 2009. PMID: 19475716
- Pinney SE, MacMullen C, Becker S. Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. The Journal of clinical investigation. 2008. PMID: 18596924
- Flanagan SE, Patch AM, Mackay DJ. Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes. 2007. PMID: 17446535
- Ellard S, Flanagan SE, Girard CA. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. American journal of human genetics. 2007. PMID: 17668386
- Gloyn AL, Siddiqui J, Ellard S. Mutations in the genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabetes mellitus and hyperinsulinism. Human mutation. 2006. PMID: 16416420
- Huopio H, Shyng SL, Otonkoski T. K(ATP) channels and insulin secretion disorders. American journal of physiology. Endocrinology and metabolism. 2002. PMID: 12110524