Complement factor H-related hybrid protein deregulates complement in dense deposit disease

Area of Science:

• Nephrology
• Immunology
• Genetics

Background:

• C3 glomerulopathy with dense deposit disease (C3G-DDD) is a severe renal disorder caused by complement system dysfunction, often leading to end-stage renal failure.
• Current treatments for C3G-DDD are ineffective, highlighting the need for understanding its underlying mechanisms.

Purpose of the Study:

• To investigate the genetic basis of C3G-DDD in a family with affected individuals.
• To elucidate the functional consequences of identified genetic variations on complement regulation.

Main Methods:

• Genetic analysis of an index family with C3G-DDD to identify causative mutations.
• Characterization of a novel hybrid complement factor H-related (CFHR) protein (CFHR2-CFHR5) using recombinant techniques.
• Assessment of the hybrid protein's effect on C3 convertase stability and regulation.
• In vitro testing of complement inhibitors (soluble CR1, eculizumab, compstatin) on patient serum.

Main Results:

• A chromosomal deletion in the CFHR gene cluster was identified, leading to the expression of a hybrid CFHR2-CFHR5 protein.
• The recombinant hybrid protein was found to stabilize C3 convertase and impair factor H-mediated decay.
• One patient showed resistance to plasma exchange therapy due to rapid re-emergence of the hybrid protein.
• Soluble CR1 effectively restored C3 convertase regulation, while eculizumab and compstatin were ineffective.

Conclusions:

• Genetic variations in the CFHR gene cluster, specifically deletions leading to hybrid CFHR proteins, are implicated in the pathogenesis of C3G-DDD.
• The hybrid CFHR2-CFHR5 protein dysregulates complement activation by stabilizing C3 convertase.
• Targeting complement regulation with agents like soluble CR1 may offer therapeutic potential for C3G-DDD patients with this specific genetic defect.