Intermittent C1-Inhibitor Deficiency Associated with Recessive Inheritance: Functional and Structural Insight

Scientific Reports
Sonia CacciaMarco Cicardi

Abstract

C1-inhibitor is a serine protease inhibitor (serpin) controlling complement and contact system activation. Gene mutations result in reduced C1-inhibitor functional plasma level causing hereditary angioedema, a life-threatening disorder. Despite a stable defect, the clinical expression of hereditary angioedema is unpredictable, and the molecular mechanism underlying this variability remains undisclosed. Here we report functional and structural studies on the Arg378Cys C1-inhibitor mutant found in a patient presenting reduced C1-inhibitor levels, episodically undergoing normalization. Expression studies resulted in a drop in mutant C1-innhibitor secretion compared to wild-type. Notwithstanding, the purified proteins had similar features. Thermal denaturation experiments showed a comparable denaturation profile, but the mutant thermal stability decays when tested in conditions reproducing intracellular crowding.Our findings suggest that once correctly folded, the Arg378Cys C1-inhibitor is secreted as an active, although quite unstable, monomer. However, it could bear a folding defect, occasionally promoting protein oligomerization and interfering with the secretion process, thus accounting for its plasma level variability. This de...Continue Reading

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Citations

Sep 14, 2019·Human Mutation·Denise PonardChristian Drouet
Mar 19, 2020·The New England Journal of Medicine·Paula J Busse, Sandra C Christiansen
Apr 5, 2020·Journal of Clinical Medicine·Jordan R YaronAlexandra R Lucas
Aug 14, 2019·Journal of Autoimmunity·Anastasios E Germenis, Marco Cicardi
Jan 29, 2021·Clinical Reviews in Allergy & Immunology·Anastasios E GermenisCamila Lopes Veronez
Jan 22, 2021·Journal of Clinical Immunology·T M Ayodele AdesanyaRami Kahwash
Jun 3, 2021·Journal of Clinical Medicine·Rosa SantacroceMaria d'Apolito
Aug 7, 2021·Scientific Reports·Sujata BuppSteven Kozlowski

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Methods Mentioned

BETA
electrophoresis
ELISA
Dot Blot
enzyme-linked immunosorbent assay
gel filtration
dot-blot
glycosylation

Software Mentioned

Rosetta online Server ( ROSIE )
MODELLER
Chimera
UCSF Chimera

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