Elucidating the Mechanism of Gain of Toxic Function From Mutant C1 Inhibitor Proteins in Hereditary Angioedema
Technical Report,30 Sep 2016,29 Sep 2017
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, however secreted C1INH levels are markedly lower than the expected 50. This project sought to determine the mechanism responsible for the low C1INH levels.We developed novel techniques that will be useful in the study of HAE. We unequivocally demonstrated that mutant C1INH induces a dominant negative effect on wild-type C1INH. We also showed that mutant C1INH induce ER stress. Finally, we show that the GOTF is not restricted to natural HAE causing mutations but appears to be intrinsic to almost any disruption of the normal C1INH structure. Our findings suggest a novel impact of misfolded proteins on secretion of wild-type proteins. These findings also suggest that abrogating the GOTF should rescue normal protein secretion and ameliorate disease.
- Anatomy and Physiology
- Medicine and Medical Research