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ATP8B1
ATPase phospholipid transporting 8B1
The ATP8B1 gene provides instructions for making a protein crucial for transporting phospholipids across cell membranes, particularly important for liver function and bile formation. The ATP8B1 gene encodes a flippase protein responsible for moving specific fat molecules within 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 vital for the normal functioning of cells throughout the body. It plays a critical role in transporting phospholipids, which are types of fats, across cell membranes. This transport mechanism is particularly important in the liver for the proper formation and flow of bile.
Changes in the ATP8B1 gene can disrupt this essential process, leading to conditions that affect bile production and release, primarily manifesting as cholestasis. These conditions are typically inherited in an autosomal recessive manner.
What the gene does
The protein encoded by the ATP8B1 gene acts as a flippase, facilitating the movement of certain phospholipids from the outer layer to the inner layer of cell membranes. This specific transport activity helps maintain the correct distribution of phospholipids within the membrane structure.
In liver cells, this function is critical for the proper transport of bile components, ensuring efficient bile production and release. Furthermore, the ATP8B1 protein helps to protect liver cells from the potentially damaging effects of bile acids, a key component of bile. Disruptions to this transport can lead to an accumulation of bile components within the liver, causing impaired liver function.
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Chromosome location
The ATP8B1 gene is located on chromosome 18, specifically at position 18q21.31. This genomic location indicates its precise address within the human genome.
Protein structure
The ATP8B1 protein consists of 1251 amino acids. It features a Disordered region spanning amino acids 1-54. This region, like other disordered domains, often plays a role in protein-protein interactions or regulatory processes.
Key variants
Variants in the ATP8B1 gene can alter the protein's ability to transport phospholipids, leading to impaired function. These genetic changes are inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to be affected.
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 inherited conditions affecting bile production and flow, collectively known as cholestasis. These include Progressive familial intrahepatic cholestasis type 1, and Benign recurrent intrahepatic cholestasis type 1, which typically involve episodes of impaired bile release. Individuals may experience symptoms such as severe itching and jaundice.
- 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 green-rated for conditions such as Cholestasis, Likely inborn error of metabolism, Neonatal cholestasis, and Undiagnosed metabolic disorders, indicating strong evidence for its role in these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ATP8B1 gene?
The ATP8B1 gene provides instructions for making a protein that acts as a flippase, transporting specific phospholipids across cell membranes. This function is particularly crucial in the liver for the formation and flow of bile, and for protecting liver cells from bile acids.
What conditions are associated with ATP8B1 gene variants?
Pathogenic variants in the ATP8B1 gene are associated with inherited cholestasis conditions, such as Progressive familial intrahepatic cholestasis type 1 and Benign recurrent intrahepatic cholestasis type 1. These conditions involve impaired bile production and release, leading to symptoms like itching and jaundice.
How is a condition related to ATP8B1 typically inherited?
Conditions caused by ATP8B1 gene variants are typically inherited in an autosomal recessive pattern. This means an individual must inherit two copies of a pathogenic gene variant, one from each parent, to develop the condition.
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