In silico analysis of alpha1-antitrypsin variants: The effects of a novel mutation

Alpha1-antitrypsin (AAT) is a highly polymorphic protein with more than 120 variants that are classified as normal (normal protein secretion), deficient (reduced circulating AAT level caused by defective secretion) or null (no protein secretion). Alpha1-antitrypsin deficiency, one of the most common genetic disorders, predisposes adults to pulmonary emphysema and, to a lesser extent, chronic liver disease and cirrhosis. In this report, we provide additional sequence data for alpha1-antitrypsin based on the characterization of a novel variant detected in a 53-year-old heterozygous patient with chronic obstructive pulmonary disease. The mutation occurred on a PI*M2 base allele and was characterized by a T → C transition at nt 97 in exon II that led to the replacement of phenylalanine by leucine (F33L). Since the mutation was found in the heterozygous state with the expression of a normally secreted variant (PI*M1) it was not possible to assess the pattern of F33L secretion. However, computational analyses based on evolutionary, structural and functional information indicated a reduction of 23 Å 3 in the side chain volume and the creation of a cavity in the protein hydrophobic core that likely disturbed the tridimensional structure and folding of AAT. The accuracy of the in silico prediction was confirmed by testing known mutations

Mise au point: déficit en alpha 1 antitrypsine

International audienceLe déficit en alpha 1 antitrypsine (AAT) est un désordre génétique commun qui se manifeste principalement par des maladies pulmonaires obstructives et plus rarement par une atteinte hépatique. La découverte de l'alpha 1 antitrypsine en tant qu'inhibiteur de protéases a abouti à la théorie du déséquilibre de la balance protéase-antiprotéase, qui demeure encore la clé de voute de la physiopathologie de l'emphysème pulmonaire. Cet article fait le point sur la pathogénèse, les facteurs de risque environnementaux et les manifestations cliniques du déficit en AAT. Des informations concernant la distribution mondiale, le diagnostic et les stratégies thérapeutiques de la maladie sont également apportées. Nous avons insisté sur l'épidémiologie du déficit en AAT dans les pays du bassin méditerranéen