Complement factor H–related hybrid protein deregulates complement in dense deposit disease
Qian Chen, … , Christine Skerka, Peter F. Zipfel
Qian Chen, … , Christine Skerka, Peter F. Zipfel
Published December 16, 2013
Citation Information: J Clin Invest. 2014;124(1):145-155. https://doi.org/10.1172/JCI71866.
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Research Article Nephrology

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

Abstract

The renal disorder C3 glomerulopathy with dense deposit disease (C3G-DDD) pattern results from complement dysfunction and primarily affects children and young adults. There is no effective treatment, and patients often progress to end-stage renal failure. A small fraction of C3G-DDD cases linked to factor H or C3 gene mutations as well as autoantibodies have been reported. Here, we examined an index family with 2 patients with C3G-DDD and identified a chromosomal deletion in the complement factor H–related (CFHR) gene cluster. This deletion resulted in expression of a hybrid CFHR2-CFHR5 plasma protein. The recombinant hybrid protein stabilized the C3 convertase and reduced factor H–mediated convertase decay. One patient was refractory to plasma replacement and exchange therapy, as evidenced by the hybrid protein quickly returning to pretreatment plasma levels. Subsequently, complement inhibitors were tested on serum from the patient for their ability to block activity of CFHR2-CFHR5. Soluble CR1 restored defective C3 convertase regulation; however, neither eculizumab nor tagged compstatin had any effect. Our findings provide insight into the importance of CFHR proteins for C3 convertase regulation and identify a genetic variation in the CFHR gene cluster that promotes C3G-DDD. Monitoring copy number and sequence variations in the CFHR gene cluster in C3G-DDD and kidney patients with C3G-DDD variations will help guide treatment strategies.

Authors

Qian Chen, Michael Wiesener, Hannes U. Eberhardt, Andrea Hartmann, Barbara Uzonyi, Michael Kirschfink, Kerstin Amann, Maike Buettner, Tim Goodship, Christian Hugo, Christine Skerka, Peter F. Zipfel

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Figure 5

Enhanced C3 convertase activity in serum of patient no. 635.

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Enhanced C3 convertase activity in serum of patient no. 635. (A) Serum o...
(A) Serum of patient no. 635 was mixed with NHS at 2% increment. Following incubation, complement activation was followed on the level of the C3 convertase by measuring C3a release and C3b deposition and on the level of C5 convertase activity by measuring C5a release and TCC surface deposition. Upon increase of NHS (20%:0%–12%:8%, serum of patient no. 635/NHS), C3a generation increased. This increase correlated with C3b deposition. At ratios of 12%:8% and 10%:10%, C3a generation and C3b deposition reached and exceeded the levels obtained achieved with NHS alone. With further increase of NHS levels and reduced patient no. 635 levels (8%:12%–0%:20%), C3a and C3b generation were decreased, and starting from ratios of 8%:12% to 0%:20%, the 2 parameters increased linearly. C5a levels showed a continuous increase and TCC surface deposition was less affected. (B) Serum of patient no. 635 (20%) was supplemented with the substrate C3 or with the combination of C3 and factor B. Following incubation for 1 hour, C3a generation was followed by ELISA and C3b surface deposition was monitored. The levels of C3a and C3b generated in NHS are indicated on the y axis. Note that in the C3 factor B–substituted serum C3a levels were higher than in NHS.