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ATP8B1
ATPase phospholipid transporting 8B1
The ATP8B1 gene provides instructions for a protein critical for transporting specific fat molecules within cell membranes, particularly in the liver, where it supports bile production and protects liver cells. ATP8B1 encodes a protein known as a flippase, which is essential for maintaining the proper distribution of phospholipids in cell membranes.
ATP8B1 is located on the long (q) arm of chromosome 18, at band 18q21.31. Arm ratio per GRCh38 - banding schematic.
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Overview
The ATP8B1 gene, also known as ATPase phospholipid transporting 8B1, is responsible for producing a protein found throughout the body. This protein plays a crucial role in maintaining cellular membrane integrity and function, particularly in the liver. It achieves this by transporting certain fat molecules across cell membranes, a process essential for normal physiological activities.
Dysfunction of the ATP8B1 protein due to genetic changes can lead to impaired bile flow, a condition known as cholestasis. Such impairments can have significant health implications, primarily affecting liver function and digestive processes.
What the gene does
The ATP8B1 gene produces a protein that belongs to a class known as flippases. Flippases are responsible for moving specific phospholipid molecules from the outer layer of a cell membrane to its inner layer. This directed movement is critical for maintaining the asymmetric distribution of phospholipids, which is vital for many cellular processes, including cell signalling and membrane trafficking.
In the liver, the ATP8B1 protein's activity is particularly important for the proper formation and secretion of bile, a digestive fluid. By ensuring the correct phospholipid balance within liver cell membranes, the protein facilitates the efficient transport of bile components. Furthermore, the ATP8B1 protein helps to shield liver cells from the potentially damaging effects of bile acids, which are a major constituent of bile. This protective role is essential for preventing liver cell injury and maintaining overall liver health.
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Chromosome location
The ATP8B1 gene is located on the long arm of chromosome 18, specifically at position 18q21.31. Chromosome 18 is one of the 23 pairs of chromosomes in humans. The precise location on this chromosome helps geneticists identify and study the gene's structure and function.
Protein structure
The ATP8B1 protein is composed of 1251 amino acids. It features a Disordered (Region) spanning amino acids 1-54. This region, typically lacking a fixed three-dimensional structure, can be involved in various functions including molecular recognition and regulation, allowing for flexibility in interactions with other molecules.
Key variants
Genetic variations within the ATP8B1 gene can alter the protein's structure and function, potentially impairing its ability to transport phospholipids or protect liver cells. These variants range from single nucleotide changes to larger deletions or duplications. Pathogenic variants are those that have been found to cause disease. The impact of a specific variant often depends on its location within the gene and how it affects the resultant 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 |
|---|---|---|---|---|
c.1246_1247del | p.His417fs | Pathogenic/Likely pathogenic | ★★☆☆ | Benign recurrent intrahepatic cholestasis type 1 |
c.1336G>A | p.Gly446Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Progressive familial intrahepatic cholestasis |
c.136C>T | p.Arg46Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cholestasis, intrahepatic, of pregnancy, 1 |
c.1473+1G>C | - | Pathogenic | ★★☆☆ | Progressive familial intrahepatic cholestasis type 1 |
c.1819+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Familial intrahepatic cholestasis |
c.212del | p.Arg71fs | Pathogenic/Likely pathogenic | ★★☆☆ | Benign recurrent intrahepatic cholestasis type 1 |
c.555-1G>C | - | Pathogenic | ★★☆☆ | Progressive familial intrahepatic cholestasis type 1 |
c.58G>T | p.Glu20Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial intrahepatic cholestasis |
c.698+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Cholestasis, intrahepatic, of pregnancy, 1 |
c.886C>T | p.Arg296Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Progressive familial intrahepatic cholestasis |
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 ATP8B1 gene are primarily associated with conditions affecting bile production and flow, collectively known as cholestasis. One notable condition is Progressive familial intrahepatic cholestasis type 1, an inherited disorder characterised by impaired bile secretion from liver cells. Other related conditions, such as benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy, have also been linked to changes in ATP8B1.
- Progressive familial intrahepatic cholestasis type 1 Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ATP8B1 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 ATP8B1 gene is included in several expert-curated panels within the UK's NHS Genomic Medicine Service via PanelApp. It is listed on panels such as Cholestasis, DDG2P, Likely inborn error of metabolism, Neonatal cholestasis, and Undiagnosed metabolic disorders, all of which are rated 'green', indicating strong evidence for its gene-disease association in these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ATP8B1 protein?
The ATP8B1 protein acts as a flippase, transporting specific phospholipid molecules from the outer to the inner leaflet of cell membranes. In the liver, this function is crucial for proper bile formation and protecting liver cells from bile acids.
What conditions are associated with pathogenic variants in ATP8B1?
Pathogenic variants in the ATP8B1 gene are linked to several cholestatic conditions, most notably Progressive familial intrahepatic cholestasis type 1. Other conditions include benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy.
How does ATP8B1 relate to liver health?
In the liver, ATP8B1 is essential for maintaining the correct distribution of fats in cell membranes, which enables proper bile secretion. It also helps protect liver cells from damage caused by bile acids, thus playing a key role in overall liver function.
References
- Cai SY, Gautam S, Nguyen T. ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. Gastroenterology. 2009. PMID: 19027009
- Davit-Spraul A, Gonzales E, Baussan C. Progressive familial intrahepatic cholestasis. Orphanet journal of rare diseases. 2009. PMID: 19133130
- Paulusma CC, de Waart DR, Kunne C. Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content. The Journal of biological chemistry. 2009. PMID: 19228692
- Adam MP, Bick S, Mirzaa GM. ATP8B1 Deficiency. 1993. PMID: 20301474