A case of remittent C1-inhibitor deficiency

C1-inhibitor is a serine protease inhibitor (serpin) controlling complement and kinin/contactsystem activation. Mutations in C1-inhibitor gene almost consistently result in reduced C1-inhibitor functional level in plasma causing hereditary angioedema, a life-threatening autosomal dominant disorder. Despite a stable defect, the clinical expression of hereditary angioedema is unpredictable, and the molecular mechanism underlyingth is variability remains undisclosed. We report a case of a patient suffering from abdominal pain and presenting markedly reduced C1-inhibitor plasma levels, episodically undergoing spontaneous normalization, car-
rying the Arg378Cys missense mutation in the serpin domain. Immunostaining analysis of patient plasma revealed the presence of C1-inhibitor oligomers, together with the occurrence of a SDS stable band that disappeared in reducing conditions, suitable for a disulphide bridged Arg378Cys homodimer. Expression studies in eukaryotic cell lines resulted in a drop in mutant C1-innhibitor secretion compared to wild type and confirmed the plasma observations. Notwithstanding, the purified recombinant proteins behave similarly. Both proteins formed stable covalent complexes with target proteases, and the kinetic of inhibition of the mutant
was just slightly diminished, although this reduction increased with temperature.Thus,our findings suggest that the Arg378Cys C1-inhibitor mutant once correctly folded should maintain the
wild type functional and structural features and instead it should bear a folding defect, abnormally susceptible to environmental factors, which may occasionally promote protein oligomerization. Moreover it can form a disulphide linked homodimer. Both these processes could account for its variability in plasma levels.