Serpinopathy

Serpinopathy (also known as serpin conformational disease or serpin polymerization disease) is a group of rare genetic disorders caused by mutations in genes encoding serine protease inhibitors (serpins). Serpins are a superfamily of proteins that regulate critical biological processes including coagulation, inflammation, and tissue remodeling. In serpinopathies, missense mutations cause the serpin protein to misfold and polymerize, forming abnormal aggregates that accumulate within cells, particularly in the endoplasmic reticulum. This leads to a toxic gain-of-function through polymer accumulation and a loss-of-function due to deficiency of the circulating active protein. The clinical manifestations of serpinopathy depend on which serpin gene is affected. The most well-characterized form involves mutations in the SERPINA1 gene (encoding alpha-1 antitrypsin), leading to alpha-1 antitrypsin deficiency, which primarily affects the liver and lungs. Liver disease results from polymer accumulation in hepatocytes, while lung disease (emphysema) results from unopposed protease activity. Other serpinopathies include familial encephalopathy with neuroserpin inclusion bodies (FENIB), caused by mutations in SERPINI1, which leads to progressive dementia and epilepsy due to neuroserpin polymer accumulation in neurons. Antithrombin deficiency (SERPINC1 mutations) can cause thrombophilia with recurrent venous thromboembolism. Treatment for serpinopathies is largely supportive and depends on the specific serpin involved. For alpha-1 antitrypsin deficiency, augmentation therapy with purified human alpha-1 antitrypsin is available, along with standard management of liver and lung disease, including liver transplantation in severe cases. For FENIB, treatment is symptomatic with antiepileptic drugs. Research into small molecules that prevent serpin polymerization and gene therapy approaches is ongoing but no curative treatments are currently available for most serpinopathies.

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