Alpha-1 antitrypsin deficiency is a rare and often underdiagnosed hereditary disorder, which mainly affects the Caucasian population. We report a case of a noncystic fibrosis bronchiectasis patient in the absence of emphysema associated with low serum alpha-1-antitrypsin (AAT) level, in the absence of the most common defective alleles associated with AAT deficiency (PI*S and PI*Z) but with a new mutation in heterozygosis. This mutation is characterized by the substitution in the coding region of exon 3, of a guanine (G) for a thymine (T), generating the replacement of a glutamine (Gln) by a histidine (His) in codon 212 (cod 212 GlnCAG > HisCAT), corresponds to a new S allelic variant. This mutation, never identified before, is called S-Napoli.
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http://dx.doi.org/10.4103/atm.ATM_234_17 | DOI Listing |
ERJ Open Res
January 2025
Kamada Ltd., Rehovot, Israel.
Background: Alpha-1 antitrypsin (AAT)-deficient individuals have a greater risk for developing COPD than individuals with normal AAT levels.
Methods: This was a double-blind, randomised, parallel group, placebo-controlled trial to examine the safety and tolerability of "Kamada-AAT for Inhalation" (inhaled AAT) in subjects with AAT deficiency, and to explore its effect on AAT and biomarkers in the lung epithelial lining fluid (ELF). 36 patients with severe AAT deficiency were randomised 2:1 to receive 80 mg or 160 mg inhaled AAT or placebo once daily for 12 weeks.
Cell Rep Med
January 2025
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA. Electronic address:
Alpha-1 antitrypsin (AAT) deficiency (AATD) is a monogenic disease caused by misfolding of AAT variants resulting in gain-of-toxic aggregation in the liver and loss of monomer activity in the lung leading to chronic obstructive pulmonary disease (COPD). Using high-throughput screening, we discovered a bioactive natural product, phenethyl isothiocyanate (PEITC), highly enriched in cruciferous vegetables, including watercress and broccoli, which improves the level of monomer secretion and neutrophil elastase (NE) inhibitory activity of AAT-Z through the endoplasmic reticulum (ER) redox sensor protein disulfide isomerase (PDI) A4 (PDIA4). The intracellular polymer burden of AAT-Z can be managed by combination treatment of PEITC and an autophagy activator.
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January 2025
Department of Cardiac Thoracic Vascular Sciences and Public Health, University of Padua, Padua, Italy.
Nat Commun
January 2025
University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
Corticosteroid binding globulin (CBG; SERPINA6) binds >85% of circulating glucocorticoids but its influence on their metabolic actions is unproven. Targeted proteolytic cleavage of CBG by neutrophil elastase (NE; ELANE) significantly reduces CBG binding affinity, potentially increasing 'free' glucocorticoid levels at sites of inflammation. NE is inhibited by alpha-1-antitrypsin (AAT; SERPINA1).
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January 2025
Physics, Department of Molecular and Translational Medicine, University of Brescia, Italy.
Neutrophil elastase (NE) is released by activated neutrophils during an inflammatory response and exerts proteolytic activity on elastin and other extracellular matrix components. This protease is rapidly inhibited by the plasma serine protease inhibitor alpha-1-antitrypsin (AAT), and the importance of this protective activity on lung tissue is highlighted by the development of early onset emphysema in individuals with AAT deficiency. As a serpin, AAT presents a surface-exposed reactive centre loop (RCL) whose sequence mirrors the target protease specificity.
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