Alpha-1-antitrypsin deficiency: Genetic variations, clinical manifestations and therapeutic interventions

Publication date: Available online 18 March 2017
Source:Mutation Research/Reviews in Mutation Research
Author(s): Younis Mohammad Hazari, Arif Bashir, Mudasir Habib, Samirul Bashir, Huma Habib, M. Abul Qasim, Naveed Nazir Shah, Ehtishamul Haq, Jeffrey Teckmane, Khalid Majid Fazili
Alpha-1-antitrypsin (AAT) is an acute phase secretory glycoprotein that inhibits neutrophil proteases like elastase and is considered as the archetype of a family of structurally related serine protease inhibitors termed serpins. Serum AAT predominantly originates from liver and increases three to five fold during host response to tissue injury and inflammation. The AAT deficiency is unique among the protein misfolding diseases in that it causes target organ injury by both loss-of-function and gain-of-toxic function mechanisms. Lack of its antiprotease activity is associated with premature development of pulmonary emphysema and loss of function due to accumulation of resultant aggregates in chronic obstructive pulmonary disease (COPD). This in turn markedly reduces the amount of AAT that is available to protect lungs against proteolytic attack by the enzyme neutrophil elastase. The coalescence of AAT deficiency, its reduced efficacy, and cigarette smoking or poor ventilation conditions have devastating effect on lung function. On the other hand, the accumulation of retained mutant proteins in endoplasmic reticulum of liver cells in a polymerized form rather than secreted into the blood in its monomeric form is associated with chronic liver disease and predisposition to hepatocellular carcinoma (HCC) by gain of toxic function. Liver injury resulting from this gain-of-toxic function mechanism in which mutant AAT retained in the ER initiates a series of pathologic events, eventually culminating at liver cirrhosis and HCC. Here in this review, we underline the structural, genetic, polymorphic, biochemical and pathological advances made in the field of AAT deficiency and further comprehensively emphasis on the therapeutic interventions available for the patient.



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