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α(1)-antitrypsin deficiency and inflammation
Ugo I Ekeowa1, Stefan J Marciniak, David A Lomas
1Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge, CB2 0XY, UK.
Expert Review of Clinical Immunology
|March 24, 2011
Summary
Alpha-1 antitrypsin deficiency, caused by SERPINA1 gene mutations, leads to protein misfolding and accumulation. This results in liver disease and early-onset emphysema, prompting new therapeutic strategies.
Area of Science:
- Genetics
- Molecular Biology
- Hepatology
Background:
- Alpha-1 antitrypsin (AAT) deficiency is an autosomal recessive disorder.
- Point mutations in the SERPINA1 gene, particularly the Z mutation (Glu342Lys), are the primary cause.
- Misfolded AAT protein forms polymers, accumulating in hepatocytes and leading to characteristic inclusions.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying AAT deficiency.
- To understand the pathogenesis of liver disease and emphysema associated with AAT deficiency.
- To explore potential therapeutic targets for AAT deficiency.
Main Methods:
- Analysis of SERPINA1 gene mutations.
- Investigation of protein misfolding and polymer formation.
- Study of cellular accumulation and extracellular effects of AAT polymers.
Main Results:
- The Z mutation causes AAT misfolding into ordered polymers, accumulating in the endoplasmic reticulum of hepatocytes.
- These polymers form periodic acid-Schiff positive inclusions, linked to neonatal hepatitis, cirrhosis, and hepatocellular carcinoma.
- Lack of circulating AAT leads to uncontrolled proteolysis, predisposing to early-onset emphysema.
Conclusions:
- AAT polymer formation in hepatocytes and extracellular tissues drives disease pathogenesis.
- Understanding these mechanisms is crucial for developing targeted therapies.
- Therapeutic strategies aim to prevent aberrant conformational transitions of mutant AAT.
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