The Cell Biology of Alpha-1 Antitrypsin Deficiency

Brittany Anderson, April Bean, Jessica Evans, Ryan Kuhl, Sam Marshall, Megan Tersteeg

Alpha-1 antitrypsin deficiency (AATD) is a complex disease resulting from a hereditary

genetic mutation of SERPINA1. This gene codes for the production of AAT in the liver and is
secreted into systemic circulation. Upon reaching the lungs, AAT inhibits the activity of
neutrophil elastase -- an enzyme responsible for breaking down elastin.11 Mutations in
SERPINA1 cause abnormal AAT to polymerize in the liver which inhibits its ability to reach the
lungs. This can lead to severe liver damage and lung disease from degradation of elastin in the
lungs.11 Because AATD symptoms are similar to those of other conditions, it is often
misdiagnosed as chronic obstructive pulmonary disease (COPD) or asthma. AATD most
commonly affects individuals of European descent, about 1 in 1,500-3,500.10,11
AATD is acquired through an autosomal codominant pattern of the SERPINA1 gene.5
Codominance occurs when both alleles are expressed and produce slightly different proteins that
affect the same genetic trait or condition.6 For example, if an individual inherits the wild-type
and mutated allele, both the functional and mutated proteins would be produced. Over 120
mutations have been reported in SERPINA1, with the most common deficiency variants being
PI*S and PI*Z (PI - Protease Inhibitor) located on the long arm of chromosome 14.10 Protease
inhibitors such as AAT work to prevent the actions of proteases, the enzymes that break down
proteins within the body.7 The most prevalent allele, PI*M, synthesizes the wild-type AAT,
while both PI*Z and PI*S are mutant alleles that produce a misfolded form of the protein.8 PI*Z,
the most common mutated allele, causes the most severe form of AATD due to a single mutation
on exon 5 leading to the substitution of the 342 glutamine for lysine.9 Furthermore, the PI*S
allele produces a mutation occurring at position 264 by replacing glutamine with valine.
Depending on the type of allele being expressed, AATD ranges in the variety and
location of symptoms. AATD is unique among protein-misfolding diseases due to its gain-of-
toxic function mechanism within the liver and its loss-of-function mechanism within the lungs,
resulting in severe symptoms in both organs.1,2 The misfolded proteins transcribed from the
inherited PI*Z allele polymerize and are retained within the ER of the hepatocytes.3,15 The
accumulation of misfolded AAT disrupts the function of the ER leading to ER stress-induced
hepatic apoptosis.4,14,15 This gain-of-toxic function results in chronic liver disease, liver scarring,
cirrhosis, and hepatocellular carcinoma.1,14 These are identified by jaundice, swelling in the legs
and abdomen, nausea, pale stools, loss of appetite, enlarged spleen, and lack of energy.13
Approximately 10% of affected infants and 15% of adults with AATD develop liver disease
and/or cirrhosis.10 This deficiency is also the most common genetic diagnosis in children
undergoing liver transplantation.10
In contrast to the pathobiology for the liver, lung damage occurs due to the lack of AAT
protein in systemic circulation.2 Even though the mutant AAT protein of the PI*S allele is
secreted from the ER, it is quickly degraded due to its instability, resulting in a lack of AAT in
the blood.9 In both mutant alleles a loss-of-function occurs due to the inability of AAT to travel
to the lungs and inhibit neutrophil elastase.5 The enzyme’s unregulated proteolytic activity can
damage the lung’s lining, connective tissue, and alveoli through elastin breakdown.3 As a result,
lung recoil is substantially reduced with each expansion and contraction. Most respiratory
symptoms of AATD appear between the age of 20-50 and include: chronic cough, fatigue,
ongoing lung infections, shortness of breath and breathing problems.12 The lung damage is
associated with the earlier development of pulmonary emphysema and the higher likelihood of
COPD for AATD patients.1,2,3 The earliest signs of AATD is shortness of breath, reduced ability
to exercise, and wheezing.10 Several lifestyle factors, like excess alcohol and smoke
consumption, lead to liver and lung cell damage and can increase the severity of the symptoms
caused by the deficiency.10
To conclude, AATD occurs due to mutations in the SERPINA1 gene that leads to the
secretion of mutant AAT proteins inherited through an autosomal codominant pattern. The
accumulation of misfolded AAT proteins in the ER of hepatocytes can lead to liver disease. Due
to the inability of mutant AAT to exit the liver, the protein cannot reach the blood and neutrophil
elastase activity is unopposed.10 Therefore, elastin in the lungs is actively broken down, leading
to lung damage and disease. AATD is both the major known genetic risk factor for lung disease
and a prominent genetic risk factor for liver disease and can be diagnosed through blood or
genetic testing.10
 References

1. Hazari, Younis Mohammad, et al. “Alpha-1-Antitrypsin Deficiency: Genetic Variations,

Clinical Manifestations and Therapeutic Interventions.” Mutation Research/Reviews in
Mutation Research, vol. 773, 2017, pp. 14–25., doi:10.1016/j.mrrev.2017.03.001.
2. Rudnick, David A., and David H. Perlmutter. “Alpha-1-Antitrypsin Deficiency: A New
Paradigm for Hepatocellular Carcinoma in Genetic Liver Disease.” Hepatology, vol. 42,
no. 3, 2005, pp. 514–521., doi:10.1002/hep.20815.
3. Brode, S. K., et al. “Alpha-1 Antitrypsin Deficiency: a Commonly Overlooked Cause of
Lung Disease.” Canadian Medical Association Journal, vol. 184, no. 12, 2012, pp. 1365–
1371., doi:10.1503/cmaj.111749.
4. Kadowaki, Hisae, and Hideki Nishitoh. “Signaling Pathways from the Endoplasmic
Reticulum and Their Roles in Disease.” Genes, vol. 4, no. 3, 2013, pp. 306–333.,
doi:10.3390/genes4030306.
5. Malintan, Nancy T., et al. “Calcium Signalling in Mammalian Cell Lines Expressing
Wild Type and Mutant Human α1-Antitrypsin.” Scientific Reports, vol. 9, no. 1, 2019,
doi:10.1038/s41598-019-53535-1.
6. “What Are the Different Ways in Which a Genetic Condition Can Be Inherited? -
Genetics Home Reference - NIH.” U.S. National Library of Medicine, National Institutes
of Health, ghr.nlm.nih.gov/primer/inheritance/inheritancepatterns.
7. “Sino Biological - Official Website.” The Function of Proteases-Enzyme,
www.sinobiological.com/research/enzymes/proteases-function.
8. Stoller, James K. “Alpha-1 Antitrypsin Deficiency.” GeneReviews® [Internet]., U.S.
National Library of Medicine, 19 Jan. 2017, www.ncbi.nlm.nih.gov/books/NBK1519/.
9. Fregonese, Laura, and Jan Stolk. “Hereditary Alpha-1-Antitrypsin Deficiency and Its
Clinical Consequences.” Orphanet Journal of Rare Diseases, BioMed Central, 19 June
2008, www.ncbi.nlm.nih.gov/pmc/articles/PMC2441617/.
10. “Alpha-1 Antitrypsin Deficiency - Genetics Home Reference - NIH.” U.S. National
Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/condition/alpha-1-
antitrypsin-deficiency.
11. Guttman, O, et al. “Acute-Phase Protein α1-Anti-Trypsin: Diverting Injurious Innate and
Adaptive Immune Responses from Non-Authentic Threats.” Clinical and Experimental
Immunology, BlackWell Publishing Ltd, Feb. 2015,
www.ncbi.nlm.nih.gov/pmc/articles/PMC4298394/.
12. “Alpha-1 Antitrypsin Deficiency.” National Heart Lung and Blood Institute, U.S.
Department of Health and Human Services, www.nhlbi.nih.gov/health-topics/alpha-1-
antitrypsin-deficiency.
 13. “Pediatric Alpha-1 Antitrypsin Deficiency: Children's Pittsburgh.” Children's Hospital of
Pittsburgh, www.chp.edu/our-services/transplant/liver/education/liver-disease-
states/alpha-1-antitrypsin-deficiency.

14. Ordóñez, Adriana, et al. “Endoplasmic Reticulum Polymers Impair Luminal Protein
Mobility and Sensitize to Cellular Stress in alpha1-Antitrypsin Deficiency.” Hepatology,
vol. 57, no. 5, 2013, pp. 2049–2060., doi:10.1002/hep.26173.

15. Miller, Stanley D.w., et al. “Tauroursodeoxycholic Acid Inhibits Apoptosis Induced by Z
Alpha-1 Antitrypsin via Inhibition of Bad.” Hepatology, vol. 46, no. 2, 2007, pp. 496–
503., doi:10.1002/hep.21689.

As members of Group 1, we all have read the entire paper and

had an opportunity to make editing suggestions for all parts. We
have agreed to submit the paper in the current form.
4 - 9 - 2020

Brittany Anderson

Ryan Kuhl

Megan Tersteeg

Sam Marshall

Jessica Evans

April Bean