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Elucidating the Mechanism of Gain of Toxic Function From Mutant C1 Inhibitor Proteins in Hereditary Angioedema

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Technical Report,30 Sep 2014,29 Sep 2015

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Veterans Medical Research Foundation San Diego United States

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HAE is autosomal dominant. Cells, heterozygous for the SERPING1 mutation, express both mutant and WT C1INH proteins.HAE is clearly a loss-of-function disease. Plasma functional C1INH levels in symptomatic HAE patients, however, are very low- far less than the predicted 50 . We have shown that this is due, at least in part, to an additional acquired GOTF defect caused by the mutant protein that interferes with the secretion of WT C1INH. Our overall hypothesis is that mutant C1INH proteins exert a variable GOTF phenotype that inhibit secretion of WT C1INH protein and worsen disease severity. This hypothesis suggests that abrogating the GOTF should result in clinical benefit. Two aims will address complementary subhypotheses.Aim 1 will assess the mechanisms of the GOTF with a hypothesis that misfolding of mutant C1INH protein in theER causes impairment of WT C1INH secretion. Elucidating the mechanism of the mutant C1INH-induced GOTF opens the possibility for new therapeutic approaches designed to abrogate the GOTF. Aim 2 will use a synthetic biology approach to assess the structural determinants of mutant C1INH-induced GOTF with a hypothesis that unique structural characteristics of C1INH make it more susceptible to GOTF than other serpins.

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