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J Clin Invest. 2019 Jan 2;129(1):388-405. doi: 10.1172/JCI98869. Epub 2018 Dec 10.

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

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Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Department of Dermatology and Allergy Centre, Odense University Hospital, Odense C, Denmark.
iPSYCH, the Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark.
Department of Cancer & Inflammation Research, University of Southern Denmark, Odense, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Unit for Thrombosis Research, Department of Regional Health Research, University of Southern Denmark and Department of Clinical Biochemistry, Hospital of South West Jutland, Esbjerg, Denmark.
Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark.


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.


Cell Biology; Genetic diseases; Genetics; Molecular genetics; Serpins

[Available on 2019-04-02]
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