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SERPINA1
serpin family A member 1
The SERPINA1 gene encodes alpha-1 antitrypsin, a protein crucial for protecting tissues, particularly the lungs, from damage caused by certain enzymes. The SERPINA1 gene provides instructions for creating the alpha-1 antitrypsin protein, a type of serine protease inhibitor.
SERPINA1 is located on the long (q) arm of chromosome 14, at band 14q32.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The SERPINA1 gene, also known as serpin family A member 1, provides the genetic blueprint for producing alpha-1 antitrypsin (A1AT), a critical protective protein in the human body. This protein is primarily synthesised in the liver and then circulates in the bloodstream to various tissues. Its main function is to inhibit the activity of certain enzymes, particularly those that can cause tissue damage if left unchecked.
A deficiency in functional alpha-1 antitrypsin can lead to a range of health issues, predominantly affecting the lungs and liver. Understanding the SERPINA1 gene and its protein is essential for comprehending the mechanisms behind conditions such as alpha-1 antitrypsin deficiency.
What the gene does
The SERPINA1 gene directs the production of alpha-1 antitrypsin, which belongs to a class of proteins called serine protease inhibitors, or serpins. These serpins are responsible for regulating various biological processes by blocking the activity of specific enzymes. Alpha-1 antitrypsin's initial identified role was to control the digestive enzyme trypsin. However, it also inhibits other powerful enzymes.
Critically, alpha-1 antitrypsin neutralises neutrophil elastase, an enzyme released by white blood cells to combat infections. While vital for immune response, neutrophil elastase can severely damage lung tissue if its activity is not properly managed. By inhibiting this enzyme, alpha-1 antitrypsin protects the lungs from destructive inflammation and tissue degradation. The protein travels through the bloodstream from its production site in the liver to the lungs and other tissues where its protective action is required.
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Chromosome location
The SERPINA1 gene is situated on chromosome 14, specifically at position 14q32.13. This chromosomal location indicates its precise address within the human genome. Genes at this locus contribute to a variety of biological functions, and the specific positioning of SERPINA1 here is consistent with its role in producing a widely distributed protein involved in enzyme inhibition.
Protein structure
The alpha-1 antitrypsin protein, encoded by the SERPINA1 gene, is composed of 418 amino acids. A key functional element within its structure is the Reactive Centre Loop (RCL), which spans amino acids 368-392. This RCL is crucial for the protein's inhibitory function, acting as a bait to trap and inactivate target enzymes like neutrophil elastase.
Key variants
Over 100 different variants within the SERPINA1 gene have been identified and linked to alpha-1 antitrypsin deficiency. These genetic changes can alter the structure or production of the alpha-1 antitrypsin protein, leading to insufficient levels or impaired function. Such variants can range from single nucleotide changes to larger deletions or insertions, all potentially impacting the protein's ability to protect tissues.
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.1130dup | p.Leu377fs | Pathogenic | ★★☆☆ | SERPINA1-related disorder |
c.1158del | p.Glu387fs | Pathogenic/Likely pathogenic | ★★☆☆ | Alpha-1-antitrypsin deficiency |
c.1178C>G | p.Pro393Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Alpha-1-antitrypsin deficiency |
c.475A>T | p.Lys159Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Alpha-1-antitrypsin deficiency |
c.480del | p.Lys160fs | Pathogenic/Likely pathogenic | ★★☆☆ | Alpha-1-antitrypsin deficiency |
c.-5+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Alpha-1-antitrypsin deficiency |
c.82del | p.Gln28fs | Pathogenic/Likely pathogenic | ★★☆☆ | Alpha-1-antitrypsin deficiency |
c.847A>T | p.Lys283Ter | Pathogenic | ★★☆☆ | Alpha-1-antitrypsin deficiency |
c.853C>T | p.Gln285Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Alpha-1-antitrypsin deficiency |
c.866dup | p.Asn289fs | Pathogenic/Likely pathogenic | ★★☆☆ | SERPINA1-related disorder |
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 SERPINA1 gene are primarily associated with Alpha-1 antitrypsin deficiency. This condition manifests when there is a shortage or dysfunction of the alpha-1 antitrypsin protein, leading to increased risk of lung and liver diseases. Individuals with this deficiency may develop lung conditions such as chronic obstructive pulmonary disease (COPD), and some may experience liver complications, including Alpha-1 antitrypsin deficiency (liver). The inheritance pattern for Alpha-1 antitrypsin deficiency is autosomal recessive.
- Alpha-1 antitrypsin deficiency (liver)
- COPD
- Alpha-1 antitrypsin deficiency Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic SERPINA1 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 SERPINA1 gene is part of the NHS Genomic Medicine Service, indicating its clinical significance in the UK. It is currently included on gene panels for Cholestasis and Pneumothorax - familial, both of which are classified as 'green' on PanelApp, signifying that there is strong evidence for their association.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is alpha-1 antitrypsin?
Alpha-1 antitrypsin is a protein primarily produced in the liver and transported through the blood. Its main role is to protect tissues, particularly the lungs, from damage caused by destructive enzymes like neutrophil elastase.
What happens if someone has a deficiency in alpha-1 antitrypsin?
A deficiency means there isn't enough functional alpha-1 antitrypsin, which can leave tissues vulnerable to damage. This most commonly leads to lung conditions such as COPD and can also cause liver problems.
How is alpha-1 antitrypsin deficiency inherited?
Alpha-1 antitrypsin deficiency is inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the SERPINA1 gene (one from each parent) to develop the condition.
References
- Gooptu B, Lomas DA. Polymers and inflammation: disease mechanisms of the serpinopathies. The Journal of experimental medicine. 2008. PMID: 18591408
- Perlmutter DH, Brodsky JL, Balistreri WF. Molecular pathogenesis of alpha-1-antitrypsin deficiency-associated liver disease: a meeting review. Hepatology (Baltimore, Md.). 2007. PMID: 17464974
- Ranes J, Stoller JK. A review of alpha-1 antitrypsin deficiency. Seminars in respiratory and critical care medicine. 2005. PMID: 16088434
- Lomas DA, Parfrey H. Alpha1-antitrypsin deficiency. 4: Molecular pathophysiology. Thorax. 2004. PMID: 15170041
- Gilis D, McLennan HR, Dehouck Y. In vitro and in silico design of alpha1-antitrypsin mutants with different conformational stabilities. Journal of molecular biology. 2003. PMID: 12498804
- Parfrey H, Mahadeva R, Lomas DA. Alpha(1)-antitrypsin deficiency, liver disease and emphysema. The international journal of biochemistry & cell biology. 2003. PMID: 12672469