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 1

Histology of kidney biopsies and the plasma parameters of patients.

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Histology of kidney biopsies and the plasma parameters of patients. (A–D...
(A–D) Kidney biopsy of patient no. 635. (A) PAS-stained kidney section illustrating prominent lobulation of the glomerular tuft, with mesangial proliferation. (B) H&E-stained kidney section with increased capillary tuft lobulation, prominent mesangial cell proliferation (asterisk), and numerous intracapillary foam cells (arrow). (C) Silver staining with double contours of the GBMs (arrow). (D) Electron microscopy of reprocessed paraffin-embedded material with abundant dense osmiophilic deposits in mesangium (white arrow) and linear dense deposits along the GBMs (black arrow). (E–H) Kidney biopsy of patient no. 638. (E) PAS-stained kidney section with prominent lobulation of the tufts and an increase in mesangial matrix and cellularity (asterisk). (F) H&E-stained kidney section, showing lobulation (asterisk). (G) C3c immunohistochemistry with intense mesangiocapillary positivity in the glomerulus. (H) TCC immunohistochemistry with a less intense positivity in the mesangium and also focally along the basement membranes. Original magnification, ×100 (A); ×400 (B, C, and E–H); ×2,156 (D). (I) Pedigree of the Erlangen family. Two related C3 glomerulopathy patients (no. 635 and no. 638) and their father (no. 634) and mother (no. 636). (J) Complement C3 and Ba fragments in plasma of the 2 patients (no. 635 and no. 638) with low C3 (303 and 331 mg/l) and increased Ba serum levels (21.3 and 21.0 mg/l). The father (no. 634) had low C3 (275 mg/l) and normal Ba levels (7.0 mg/l). The mother and a healthy individual had normal C3 (1,309 and 1,273 mg/l) and Ba levels (5.0 mg/l).