Pathogenic Factor XII Mutations: Form Dertermines Dysfunction
Coen Maas, Ph.D.
University Medical Center Utrecht
Utrecht, the Netherlands
Pathogenic Factor XII Mutations: Form Determines Dysfunction
Factor XII (FXII) drives intrinsic coagulation and bradykinin production when blood contacts unnatural surface materials. It was identified as a potential therapeutic target for thrombosis with a desirable safety profile.
FXII has the following domain organization: FnII--EGF1--FnI--EGF2—Kringle-PRR--Protease.
Cleavage after R353 (in the protease activation loop) functions as an “on-switch” for full activation. The distant FnII domain protects it, indicating that FXII assumes a closed conformation. Binding to surfaces and receptors opens it up.
Gain-of-function mutations in FXII lead to inflammatory disease without thrombosis. Substitution mutations in the proline-rich region (PRR) result in hereditary angioedema (HAE-FXII), which is associated with aggressive, acute, and localized attacks of tissue swelling. These mutations introduce additional cleavage sites. Premature truncation exposes the activation loop, which propagates bradykinin formation. Recently, a new mutation in the Kringle domain (W268R) was found in a family with cold-induced urticarial rash and systemic inflammation. Patients with FXII-associated cold autoinflammatory syndrome (FACAS) experience continuous systemic contact system activation and bradykinin-dependent disease. The FACAS mutation causes FXII to adopt an open conformation (exposing the activation loop). As a result, it already shows signs of autoactivation in the cells that produce it, and it displays enzymatic activity during secretion.
The combined studies indicate that a conformational switching of FXII is important for its function. Inappropriate exposure of the activation loop, whether continuous (FACAS) or temporarily (HAE-FXII), leads to bradykinin-driven pathology.