Thematic series “Alpha-1 antitrypsin deficiency” - Article in English and French
Coordinated by J.-F. Mornex and A. Cuvelier
Molecular pathogenesis of alpha-1-antitrypsin deficiencyBases moléculaires du déficit en alpha-1 antitrypsine

https://doi.org/10.1016/j.rmr.2014.03.015Get rights and content

Summary

Alpha-1 antitrypsin (α1-AT) is the most abundant circulating protease inhibitor. The common severe Z allele of α1-AT (Glu342Lys) causes the protein to form ordered polymers that are retained within the endoplasmic reticulum of hepatocytes. These polymers form the periodic acid-Schiff positive inclusions that are associated with cirrhosis. The lack of circulating α1-AT predisposes the Z α1-AT homozygote to early onset emphysema. We review here the molecular basis of α1-AT deficiency and show how understanding the liver disease provides new insights in the pathobiology of the associated emphysema. The mechanism of α1-AT deficiency provides a paradigm for a wider group of conditions that we have termed the serpinopathies. We also examine the strategies that are being pursued to develop novel therapies for α1-AT deficiency. This review considers our understanding of the pathobiology of α1-AT deficiency and then illustrate the therapeutic possibilities that can ensue once we understand basic mechanisms of disease.

Résumé

L’alpha-1 antitrypsine1-AT) est le principal inhibiteur circulant des protéases. La mutation délétère de l’allèle Z de l’α1-AT (Glu342Lys) entraîne la formation de polymères ordonnés de la protéine qui sont séquestrés à l’intérieur du réticulum endoplasmique des hépatocytes. Ces polymères forment des inclusions PAS (acide périodique de Schiff) positives qui sont associées à une cirrhose. Le déficit en α1-AT circulante prédispose les individus homozygotes pour l’allèle Z de l’α1-AT au développement précoce d’un emphysème pulmonaire. Dans ce manuscrit, nous passons en revue les bases moléculaires du déficit en α1-AT et montrons comment la compréhension de la maladie hépatique apporte de nouvelles perspectives aux modifications physio-pathologiques qui conduisent à l’emphysème associé. Le mécanisme sous-jacent au déficit en α1-AT permet de proposer un paradigme à un groupe plus important de pathologies que nous avons appelées les serpinopathies. Nous abordons également les stratégies de développement des nouvelles thérapies pour traiter le déficit en α1-AT. Cette revue porte sur notre compréhension de la biopathologie du déficit en α1-AT et illustre les possibilités thérapeutiques pouvant découler de notre compréhension des mécanismes fondamentaux de la maladie.

Section snippets

English version

Alpha-1 antitrypsin (α1-AT) is synthesized by the liver and is present in the plasma at a concentration of 1.5–3.5 g/L. It functions primarily as an inhibitor of the enzyme neutrophil elastase. Most individuals are homozygous for the M allele with the commonest deficiency alleles being the severe Z (Glu342Lys) and the mild S (Glu264Val) variants. The Z mutation causes α1-AT to be degraded by endoplasmic reticulum-associated degradation (ERAD) or retained within hepatocytes as polymers that form

Version française

L’alpha-1 antitrypsine (α1-AT) est synthétisée par le foie et ses concentrations plasmatiques varient de 1,5 à 3,5 g/L. Sa principale fonction est d’inhiber l’élastase produite par les neutrophiles. La plupart des individus sont homozygotes pour l’allèle sauvage M, les allèles les plus fréquents entraînant un déficit sévère ou léger en α1-AT étant respectivement l’allèle Z (Glu342Lys) et l’allèle S (Glu264Val). La mutation Z entraîne une dégradation de l’α1-AT par la machinerie de dégradation

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