The following is a summary of “Restriction of C1-inhibitor activity in hereditary angioedema by dominant-negative effects of disease-associated SERPING1 gene variants,” published in the NOVEMBER 2023 issue of Allergy & Immunology by Ryø, et al.
Hereditary angioedema is a rare genetic disorder characterized by recurrent and potentially life-threatening edema attacks. The majority of cases result from genetic variants in the SERPING1 gene, causing a deficiency in the C1 inhibitor (C1INH) protein. Despite identifying over 500 disease-causing variants, the mechanisms leading to pathologically low C1INH levels remain unclear. For a study, researchers sought to characterize trans-inhibitory effects of full-length or near full-length C1INH encoded by 28 disease-associated SERPING1 variants.
HeLa cells were transfected with constructs encoding the studied SERPING1 variants, and comprehensive analyses of C1INH expression, secretion, functionality, and intracellular localization were conducted.
The findings classified the SERPING1 variants into five clusters based on shared molecular characteristics. Except for two variants, mutant and normal C1INH coexpression negatively impacted the overall ability to target proteases. Intriguingly, a subset of variants exhibited intracellular formation of C1INH foci only in heterozygous configurations, where normal and mutant C1INH were expressed simultaneously.
The study presented a functional classification of SERPING1 gene variants, suggesting diverse molecular disease mechanisms. For some variants, the data indicated hereditary angioedema with C1INH deficiency as serpinopathies driven by dominant-negative mechanisms.
Source: jacionline.org/article/S0091-6749(23)00750-9/fulltext
