Alpha-1-antitrypsin (AAT) is a protein that protects the body from
damage by its immune cells. Deficiency of this protein leaves the lung,
and occasionally the liver, vulnerable to injury.
The lung is made of thin outpouchings called alveoli. These contain
air, and oxygen travels across their walls into the bloodstream.
White blood cells release elastase, a powerful enzyme that can fight
infections. But it can also attack normal tissues. If uncontrolled
elastase is released around alveoli, it would destroy their walls and
surrounding tissue, leaving areas of trapped air. This abnormal
accumulation of air in the lungs is called emphysema and causes shortness
AAT inhibits elastase around normal tissue. Deficiency is caused by
mutations in the SERPINA1 gene, located on chromosome 14. This gene has
many different versions (alleles) that produce different amounts of AAT.
The M allele produces normal levels of the AAT protein, the S allele
produces moderately low levels, and the Z allele produces very low
The alleles are expressed in a codominant manner that means
that a person with MZ has levels of AAT that are between the levels of
those people who have alleles MM or ZZ.
Individuals who have at least one normal allele (MZ or MS) or two
copies of S (SS) usually produce enough AAT to protect the lungs but do
have an increased risk of lung disease. The risk is particularly high if
they smoke. Individuals who inherit the Z allele from each parent (ZZ)
have very low AAT and are at a higher risk of developing emphysema and
There are over 70 known mutations that occur at the SERPINA1 gene. A
common mutation that creates the Z allele involves a switch in amino acids
glutamic acid is replaced by lysine at position 342 (Glu342Lys).
The resulting AAT protein cannot fold properly. This hinders its secretion
from the liver (which makes AAT) into the bloodstream (which transports
AAT to the lungs). The accumulation of AAT complexes can damage the liver,
whereas the lack of AAT fails to stop the destruction of lung tissue.
Treatment of AAT deficiency includes the standard treatmet of emphysema (bronchodilators,
early use of antibiotics in infections) as well as the more experimental therapies
of correcting AAT levels by replacing the protein. Gene therapy to replace
the defective SERPINA1 gene with a functional copy is currently being investigated.
However, the most important part of treatment of AAT deficiency is to avoid
smoking. Affected individuals are far less likely to develop emphysema if
they do not smoke. Not only is smoking a lung irritant, which attracts white
blood cells (and therefore neutrophil elastase) to the lungs, it also prevents
any AAT that is present in the lungs from working properly.
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