Molecular mousetraps, α₁-antitrypsin deficiency and the serpinopathies

Abstract

Point mutations in members of the serine proteinase inhibitor or serpin superfamily cause them to change shape, polymerise and be deposited in the tissues. This process is best seen in mutants of α₁-antitrypsin within hepatocytes to cause periodic acid-Schiff (PAS) positive inclusions and cirrhosis. An identical process underlies the PAS positive inclusions of mutants of neuroserpin within neurones to cause a dementia that we have called familial encephalopathy with neuroserpin inclusion bodies (FENIB). In both cases, there is a direct correlation between the molecular instability, the rate of intracellular polymer formation and the severity of disease. This process of polymerisation also explains the failure to secrete mutants of other members of the serpin superfamily – antithrombin, C1 inhibitor and α₁-antichymotrypsin – to cause thrombosis, angio-oedema and emphysema, respectively. In view of the common mechanism underlying these conditions, we have grouped them together as the serpinopathies.