C1 inhibitor hinge region mutations produce dysfunction by different mechanisms

Alvin E. Davis, Kulwant Aulak, Richard B. Parad, Hilary P. Stecklein, Eric Eldering, C. Erik Hack, Judit Kramer, Robert C. Strunk, John Bissler, Fred S. Rosen

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Heterozygosity for a mutant dysfunctional C1 inhibitor protein, a member of the serine proteinase inhibitor (serpin) superfamily, results in type II hereditary angioneurotic oedema. We identified a “hinge” region mutation in C1 inhibitor with a Val to Glu replacement at P14 Val–432. Recombinant C1 inhibitors P10 Ala→Thr and P14 Val→Glu did not form stable complexes with fluid phase C1s or kallikrein. The P14 Val→Glu mutant, however, was cleaved to a 96K form by C1s, while the P10 Ala→Thr mutant was not. The recombinant P10 mutant also did not complex with C1s, kallikrein or β–factor XIIa–Sepharose. The two mutations, therefore, result in dysfunction by different mechanisms: in one (P14 Val→Glu), the inhibitor is converted to a substrate, while in the other (P10 Ala→Thr), interaction with target protease is blocked.

Original languageEnglish
Pages (from-to)354-358
Number of pages5
JournalNature genetics
Issue number5
Publication statusPublished - Aug 1992

ASJC Scopus subject areas

  • Genetics

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    Davis, A. E., Aulak, K., Parad, R. B., Stecklein, H. P., Eldering, E., Hack, C. E., Kramer, J., Strunk, R. C., Bissler, J., & Rosen, F. S. (1992). C1 inhibitor hinge region mutations produce dysfunction by different mechanisms. Nature genetics, 1(5), 354-358. https://doi.org/10.1038/ng0892-354