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C1 inhibitor hinge region mutations produce dysfunction by different mechanisms.
A E Davis1, K Aulak, R B Parad
1Division of Nephrology, Children's Hospital Research Foundation, Cincinnati, Ohio.
Nature Genetics
|August 1, 1992
Summary
Mutations in the C1 inhibitor protein cause hereditary angioneurotic oedema. Researchers found two distinct mutations leading to dysfunctional C1 inhibitor, affecting its interaction with proteases differently.
Area of Science:
- Biochemistry
- Immunology
- Genetics
Background:
- Type II hereditary angioneurotic oedema is linked to dysfunctional C1 inhibitor protein.
- C1 inhibitor is a crucial member of the serine proteinase inhibitor (serpin) superfamily.
Purpose of the Study:
- To investigate the functional impact of specific mutations in the C1 inhibitor.
- To elucidate the molecular mechanisms underlying C1 inhibitor dysfunction in hereditary angioneurotic oedema.
Main Methods:
- Site-directed mutagenesis to create recombinant C1 inhibitor variants (P10 Ala-->Thr and P14 Val-->Glu).
- Assays to assess complex formation between mutant C1 inhibitors and target proteases (C1s, kallikrein, beta-factor Xlla).
- Analysis of cleavage products of C1 inhibitor mutants by C1s.
Main Results:
- Both P10 Ala-->Thr and P14 Val-->Glu mutants failed to form stable complexes with fluid phase C1s and kallikrein.
- The P14 Val-->Glu mutant was cleaved by C1s into a 96K form, indicating conversion to a substrate.
- The P10 Ala-->Thr mutant did not interact with C1s, kallikrein, or beta-factor Xlla-Sepharose, suggesting blocked protease interaction.
Conclusions:
- The P14 Val-->Glu mutation leads to C1 inhibitor dysfunction by converting it into a substrate for C1s.
- The P10 Ala-->Thr mutation results in C1 inhibitor dysfunction by preventing its interaction with target proteases.
- These findings clarify distinct molecular mechanisms of C1 inhibitor dysfunction in hereditary angioneurotic oedema.