Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema.

Didde Haslund,Laura Barrett Ryø,Yaseelan Palarasah,Anja Bille Bohn,Kristian Alsbjerg Skipper,Iben Rose,Tue Fryland,Sara Seidelin Majidi,Claus Koch,Lene N Nejsum,Thomas J Corydon,Jacob Giehm Mikkelsen,Martin K Thomsen,Anette Bygum

doi:10.1172/jci98869

Abstract

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent edema attacks associated with morbidity and mortality. HAE results from variations in the SERPING1 gene that encodes the C1 inhibitor (C1INH), a serine protease inhibitor (serpin). Reduced plasma levels of C1INH lead to enhanced activation of the contact system, triggering high levels of bradykinin and increased vascular permeability, but the cellular mechanisms leading to low C1INH levels (20%-30% of normal) in heterozygous HAE type I patients remain obscure. Here, we showed that C1INH encoded by a subset of HAE-causing SERPING1 alleles affected secretion of normal C1INH protein in a dominant-negative fashion by triggering formation of protein-protein interactions between normal and mutant C1INH, leading to the creation of larger intracellular C1INH aggregates that were trapped in the endoplasmic reticulum (ER). Notably, intracellular aggregation of C1INH and ER abnormality were observed in fibroblasts from a heterozygous carrier of a dominant-negative SERPING1 gene variant, but the condition was ameliorated by viral delivery of the SERPING1 gene. Collectively, our data link abnormal accumulation of serpins, a hallmark of serpinopathies, with dominant-negative disease mechanisms affecting C1INH plasma levels in HAE type I patients, and may pave the way for new treatments of HAE.

Highlights

Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease with an estimated prevalence of 1:50,000 to 1:70,000 worldwide [1,2,3]
The reduced plasma C1 inhibitor (C1INH) level in patients diagnosed with HAE type I suggests that the C1INH level in the blood of HAE patients is affected by mechanisms contributing to development of the disease
To investigate if such mechanisms contribute to reduced plasma C1INH levels in HAE type I patients, we initially investigated a total of 6 HAE type I–causing SERPING1 gene variants present in Danish HAE patients

Summary

Introduction

Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease with an estimated prevalence of 1:50,000 to 1:70,000 worldwide [1,2,3]. Attacks often involve the extremities, the face, the gastrointestinal tract, and less frequently, but potentially life-threatening, the larynx [4]. If not fatal, these very painful attacks are self-limiting and last up to 5 days. HAE is caused by variants of the serpin family G member 1 (SERPING1) gene encoding the serine protease inhibitor (serpin) C1 inhibitor (C1INH) [5]. More than 450 different HAE-causing SERPING1 gene variants have been identified, leading to either low levels (in the case of HAE type I) or reduced function (in the case of HAE type II) of C1INH [2, 6].

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