Alpha-1 antitrypsin deficiency (A1ATD) causes lung disease and liver disease. Affected individuals often develop emphysema, the appearance of which is accelerated by smoking or exposure to tobacco smoke. About 10 percent of infants with alpha-1 antitrypsin deficiency develop liver disease, which often causes jaundice. Approximately 15 percent of adults with alpha-1 antitrypsin deficiency develop cirrhosis; affected individuals are also at risk of developing hepatocellular carcinoma. In rare cases, people with alpha-1 antitrypsin deficiency develop panniculitis, a skin condition characterized by hardened skin with painful lumps or patches. [from Genetics Home Reference, GHR:condition:alpha-1-antitrypsin-deficiency 2016.3.1]

The most common manifestation of alpha-1-antitrypsin deficiency is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age (Crystal, 1990, pubmed:2696185). [from MIM:613490, 2016.2.29]

alpha-1-antitrypsin deficiency is caused by mutations in the SERPINA1 gene and it is inherited in a codominant pattern. Over 120 different mutations in the SERPINA1 gene have been identified, with the most common termed S and Z, whereas the normal allele of the gene is termed M. The S allele produces moderately low levels of protein and the Z allele produces very little protein. Rare null variants (producing no protein) have also been identified. ZZ individuals are at high risk of developing emphysema. SZ individuals have an increased risk of developing lung diseases, particularly if they smoke. Alpha-1 antitrypsin deficiency occurs worldwide, but its prevalence varies by population. This disorder affects about 1 in 1,500 to 3,500 individuals with European ancestry. It is uncommon in people of Asian descent. Many individuals with alpha-1 antitrypsin deficiency are likely undiagnosed. [from NORD, http://rarediseases.org/rare-diseases/alpha-1-antitrypsin-deficiency/ and Genetics Home Reference, GHR:condition:alpha-1-antitrypsin-deficiency 2016.3.1]

Alpha-1-antitrypsin deficiency is an autosomal recessive disorder.; it has been shown to be caused by mutations in the SERPINA1 gene, which encodes alpha-1-antitrypsin. Multiple allelic variants have been characterized including M, S, Z, F, I, V, and Q0. Individuals with the M allele are unaffected. The most common AAT deficiency allele is the Z allele (glu342lys); ZZ homozygotes are associated with a high risk of both emphysema and liver disease. Another common AAT deficiency allele is the S allele (glu264val); S homozygotes are at no risk of emphysema, but compound heterozygotes with a Z or a null allele have a mildly increased risk. [from MIM:613490, 2016.2.29]

Alpha-1 antitrypsin (A1AT) is a serine protease inhibitor whose targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. [from Gene Cards, http://www.genecards.org/cgi-bin/carddisp.pl?gene=SERPINA1 2016.2.29]

The Z mutation (Glu342Lys) favors the spontaneous formation of polymers between the reactive center loop of one molecule and beta-sheet A of another. These polymers are retained within hepatocytes to form inclusion bodies that are associated with neonatal hepatitis, cirrhosis, and hepatocellular carcinoma (FBrf0155704).

Alpha-1 antitrypsin controls neutrophil elastase, a serine protease that is released from white blood cells to fight infection, but can attack normal tissues (especially the lungs) if not tightly controlled by alpha-1 antitrypsin. Mutations in the SERPINA1 gene can lead to low levels or abnormal forms of alpha-1 antitrypsin that are insufficient to control neutrophil elastase. Without enough functional alpha-1 antitrypsin, neutrophil elastase destroys alveoli and causes lung disease. Abnormal alpha-1 antitrypsin can also accumulate in the liver causing scarring damage. [from Genetics Home Reference, GHR:condition:alpha-1-antitrypsin-deficiency 2016.3.1]

The SERPINA1 gene encodes alpha-1-antitrypsin (AAT), a major plasma serine protease inhibitor. AAT complexes predominantly with elastase, but also with trypsin, chymotrypsin, thrombin, and bacterial proteases. The most important inhibitory action of AAT is that against neutrophil elastase, a protease that degrades elastin of the alveolar walls as well as other structural proteins of a variety of tissues (Cox et al. 2001. The Metabolic and Molecular Bases of Inherited Disease. Vol. IV. New York: McGraw-Hill (8th ed.): pp. 5559-5584). [from MIM:107400, 2016.3.1]