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Animals, Endoplasmic Reticulum, Genetic Predisposition to Disease, Heterozygote, Humans, Lung, Lung Diseases, Mutation, Peptide Hydrolases, Phenotype, Pulmonary Disease, Chronic Obstructive, Risk Assessment, Risk Factors, Smoking, Stress, Physiological, alpha 1-Antitrypsin, alpha 1-Antitrypsin Deficiency


The Version of Scholarly Record of this Article is published in Expert Review of Respiratory Medicine 2011, available online at: DOI: 10.1586/ers.11.20


The serine proteinase inhibitor α-1 anti-trypsin (AAT) provides an antiprotease protective screen throughout the body. Mutations in the AAT gene (SERPINA1) that lead to deficiency in AAT are associated with chronic obstructive pulmonary diseases. The Z mutation encodes a misfolded variant of AAT that is not secreted effectively and accumulates intracellularly in the endoplasmic reticulum of hepatocytes and other AAT-producing cells. Until recently, it was thought that loss of antiprotease function was the major cause of ZAAT-related lung disease. However, the contribution of gain-of-function effects is now being recognized. Here we describe how both loss- and gain-of-function effects can contribute to ZAAT-related lung disease. In addition, we explore how SERPINA1 heterozygosity could contribute to smoking-induced chronic obstructive pulmonary diseases and consider the consequences.


Medicine and Health Sciences


Greene CM, Hassan T, Molloy K, McElvaney NG. The role of proteases, endoplasmic reticulum stress and SERPINA1 heterozygosity in lung disease and α-1 anti-trypsin deficiency. Expert Review of Respiratory Medicine. 2011;5(3):395-411

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