Restriction of C1-inhibitor activity in hereditary angioedema by dominant-negative effects of disease-associated SERPING1 gene variants

Abstract

Patients with hereditary angioedema (HAE) experience recurrent, sometimes life-threatening, attacks of edema. It is a rare genetic disorder characterized by genetic and clinical heterogenicity. Most cases are caused by genetic variants in the SERPING1 gene leading to plasma deficiency of the encoded protein C1 inhibitor (C1INH). More than 500 different HAE-causing variants have been identified in the SERPING1 gene, but the disease mechanisms by which they result in pathologically low C1INH plasma levels remain largely unknown. The aim is to describe trans-inhibitory effects of full-length or near full-length C1INH encoded by 28 disease-associated SERPING1 variants. HeLa cells are transfected with expression constructs encoding the studied SERPING1 variants. Extensive and comparative studies of C1INH expression, secretion, functionality, and intracellular localisation are carried out. Our findings characterize functional properties of a subset of SERPING1 variants allowing the examined variants to be subdivided into five different clusters, each containing variants sharing specific molecular characteristics. For all variants, except two, we find that co-expression of mutant and normal C1INH negatively impacts the overall capacity to target proteases. Strikingly, for a subset of variants, intracellular formation of C1INH foci is detectable only in heterozygous configurations enabling simultaneous expression of normal and mutant C1INH. We provide a functional classification of SERPING1 gene variants suggesting that different SERPING1 variants drive the pathogenicity through different and in some cases overlapping molecular disease mechanisms. For a subset of gene variants, our data define some types of C1INH-HAE as serpinopathies driven by dominant-negative disease mechanisms.