SERPINA1 (Serpin Family A Member 1)

Overview

SERPINA1 encodes Alpha-1 Antitrypsin (AAT), a serine protease inhibitor (serpin) primarily produced in the liver. AAT protects the lungs from damage caused by neutrophil elastase, an enzyme released during inflammation. Mutations lead to Alpha-1 Antitrypsin Deficiency (AATD), one of the most common genetic causes of lung and liver disease.

📍 Chromosomal Position

14q32.13 (Chromosome 14)

🧬 Gene Category

Hereditary Diseases

🔬 Inheritance

Codominant

📊 Prevalence

PiZZ: ~1:2,500 in Northern Europe, PiMZ (Carrier): ~1:25

Function & Significance

Alpha-1 antitrypsin is synthesized in the liver and transported via the blood to the lungs, where it inhibits neutrophil elastase. This enzyme is released by white blood cells during inflammation and can break down lung tissue. AAT protects the lungs from this enzymatic attack.

In mutations such as PiZ, the AAT protein is misfolded and polymerizes in the liver instead of being released into the blood. This leads to two problems: (1) deficiency of AAT in the lungs → unchecked elastase activity → emphysema, and (2) accumulation of misfolded protein in the liver → liver damage → cirrhosis.

🔬 Pi System (Protease Inhibitor)

The Pi system classifies AAT variants according to their electrophoretic mobility:

PiMM: Normal (two M alleles)
PiMZ: Carrier (one M, one Z) – 60-80% normal AAT levels
PiZZ: Severe deficiency – 10-15% normal AAT levels
PiSS: Mild deficiency – ~60% normal AAT levels
PiSZ: Moderate deficiency – 40% normal AAT levels

Associated Diseases

🫁 Emphysema / COPD

Panacinar emphysema, especially in PiZZ. Early onset (30-40 years), accelerated by smoking.
🩺 Liver Cirrhosis

Accumulation of polymerized AAT in hepatocytes leads to liver damage. Can occur as early as childhood.
👶 Neonatal Cholestasis

Jaundice in newborns with PiZZ, usually self-limiting
🔬 Hepatocellular Carcinoma

Increased risk in cases of liver cirrhosis

🧬 Relevant SNPs

rs28929474
14:94844947

Allele 1

Allele 2

Significance: PiZ (E342K, Glu342Lys) – Most common severe variant. The mutated protein polymerizes and is retained in the liver. PiZZ genotype leads to 10-15% normal AAT blood levels and a high risk for emphysema (especially in smokers) and liver cirrhosis.

rs17580
14:94844738

Allele 1

Allele 2

Significance: PiS (E264V, Glu264Val) – Milder variant. The protein is degraded intracellularly more rapidly. PiSS genotype has ~60% normal AAT levels, usually sufficient for lung protection. PiSZ (compound heterozygote) leads to ~40% AAT levels and moderate risk.

⚕️ Clinical Significance & Therapy

Diagnosis: Measure blood AAT levels, genotyping for confirmation. Screening recommended for early emphysema, unexplained liver cirrhosis, or positive family history.

Augmentation Therapy: Weekly or monthly infusions of purified AAT from donor plasma can normalize AAT levels and slow emphysema progression. Only approved for PiZZ and PiSZ with proven emphysema.

Additional Measures:

Smoking Cessation: Absolutely critical! Smoking massively accelerates emphysema development
Vaccinations: Pneumococcal, Influenza, COVID-19
Liver Transplantation: In cases of advanced cirrhosis
Lung Transplantation: In end-stage COPD

Genetic Counseling: PiMZ carriers should not smoke and avoid dust exposure. Prenatal diagnosis is possible.

📚 Data Sources

The information on this page is based on the following scientific sources:

OMIM: #613490 (Alpha-1-Antitrypsin Deficiency)
dbSNP: rs28929474 (PiZ), rs17580 (PiS)
ClinVar: Pathogenic SERPINA1 variants
PubMed: Literature on Alpha-1 Antitrypsin deficiency
Alpha-1 Foundation: alpha1.org
European Respiratory Society: AAT Guidelines

Last Update: February 2026

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SERPINA1