Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

You are here: Molecular Genetics » Alpha-1 Antitrypsin Deficiency

Alpha-1 Antitrypsin Deficiency [E88.0]

OMIM numbers: 613490, 107400 (SERPINA1)

Dr. rer. nat. Karin Mayer, Dipl.-Biol. Christine Schack,
Dipl.-Biol. Christina Sofeso

Scientific Background

Alpha-1 antitrypsin (AAT) deficiency is an autosomal recessive disease characterized by pulmonary emphysema and liver cirrhosis with variable clinical presentation. Serum levels of alpha-1 antitrypsin are reduced. Alpha-1 antitrypsin is encoded by the SERPINA1 (PI) gene and functions as an important protease inhibitor. A deficiency leads to a reduced inhibition of neutrophilic elastase and therefore, to increased lysis of the elastine and of the collagen from the alveolar walls, especially during pulmonary infections.

The polymorphic SERPINA1 gene is distinguished in 3 allele types: normal (M), deficiency (Z, S) and null. The PI*Z allele (Glu342Lys) represents with a prevalence of 1–5% in Europeans the most common PI allele and is most frequently found in Skandinavia. Homozygous ZZ carriers (prevalence 1:2,000–1:7,000) show a 10–15% lower serum concentration of alpha-1 antitrypsin and therefore exhibit a significantly increased risk for chronic obstructive pulmonary disease (COPD). In addition, large amounts of the protein accumulate in hepatocytes, which can lead to cell damage and liver cirrhosis. In about 10% of the carriers the deficiency already manifests in early infancy as neonatal hepatic syndrome with jaundice. Heterozygous MZ carriers show a decreased alpha-1 antitrypsin serum concentration as well, the risk for COPD is increased. The frequency of the PI*S allele (Glu264Val) is about 2–4% in Europe, being highest on the Iberian Peninsula. Heterozygous SZ carriers bear a risk of COPD that lies between the one of MZ and ZZ carriers. Homozygous and heterozygous carriers of the S allele generally do not have an increased risk for pulmonary or hepatic disease. Cigarette smoke is considered the main risk factor for COPD in carriers of a PI* "at risk" allele. Null alleles are very rare, they are caused by stop or splice mutations as well as deletions in the SERPINA1 gene.