Intermittent C1-Inhibitor Deficiency Associated with Recessive Inheritance: Functional and Structural Insight

Area of Science:

• Biochemistry
• Molecular Biology
• Immunology

Background:

• C1-inhibitor (C1-INH) regulates complement and contact systems.
• Mutations in C1-INH cause hereditary angioedema (HAE), a disorder with unpredictable clinical severity.
• The molecular basis for HAE variability in C1-INH deficiency remains unclear.

Purpose of the Study:

• Investigate the functional and structural properties of the Arg378Cys C1-INH mutant.
• Elucidate the molecular mechanisms underlying plasma level variability in HAE.
• Determine how the Arg378Cys mutation affects C1-INH secretion, stability, and function.

Main Methods:

• Functional and structural studies of the Arg378Cys C1-INH mutant.
• Expression studies to assess C1-INH secretion.
• Purification and characterization of mutant C1-INH.
• Thermal denaturation experiments under varying conditions (including intracellular crowding).

Main Results:

• The Arg378Cys mutation reduces C1-INH secretion compared to wild-type.
• Purified Arg378Cys C1-INH exhibits similar features to wild-type but reduced thermal stability in crowded conditions.
• The mutation can lead to non-functional homodimer formation via disulfide bonds.
• Protein misfolding and oligomerization potentially interfere with secretion, explaining plasma level variability.

Conclusions:

• The Arg378Cys C1-INH mutant is secreted as an unstable monomer but may possess a folding defect.
• This defect can lead to oligomerization, impaired secretion, and plasma level variability in HAE patients.
• Environmental conditions and acquired cysteine residues exacerbate C1-INH instability and dysfunction.