Alpha1-Antitrypsin Deficiency- A comprehensive review by NEJ
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Alpha1-antitrypsin (AAT) deficiency is one of the most common genetic diseases. Most persons carry two copies of the wild-type M allele of SERPINA1, which encodes AAT, and have normal circulating levels of the protein. Ninety-five percent of severe cases of AAT deficiency result from the homozygous substitution of a single amino acid, Glu342Lys (the Z allele), which is present in 1 in 25 persons of European descent (1 in 2000 persons of European descent are homozygotes). Mild AAT deficiency typically results from a different amino acid replacement, Glu264Val (the S allele), which is found in 1 in 4 persons in the Iberian peninsula.

However, many other alleles have been described that have variable effects, such as a lack of protein production (null alleles), production of misfolded protein, or no effect on the level or function of circulating AAT. AAT is synthesized in the liver and secreted into the circulation, where its primary role is to protect lung tissue against attack by the enzyme neutrophil elastase. Point mutations can lead to retention of AAT in the liver, causing liver disease through a toxic “gain of function,” whereas the lack of an important circulating proteinase inhibitor predisposes homozygotes with severe deficiency to early-onset emphysema (“loss of function”).

The high frequency of genetic variants suggests that AAT mutations confer a selective advantage, perhaps by amplifying the inflammatory response to invasive respiratory and gastrointestinal infection. This review discusses the current understanding of the pathophysiology of AAT deficiency and discuss how this knowledge has led to new therapeutic strategies.