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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 Article has an altmetric score of 33

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

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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 2

A novel chromosomal deletion in the CFHR2 gene of 2 related patients with C3 glomerulopathy.

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A novel chromosomal deletion in the CFHR2 gene of 2 related patients wit...
(A) MLPA. DNA of patients (no. 635 and no. 638, red) and the father (no. 634, blue) showed a heterozygous deletion of CFHR2 exon IV on chromosome 1q32. DNA of the mother (no. 636, orange) and a healthy individual (gray) presented with 2 copies. (B) Chromosomal breakpoint in the CFHR2-CFHR5 region. The sequence of the PCR product generated from DNA of patients using inverse-nested PCR is shown. The presented nucleotides 1–15 correspond to intron III of CFHR2 gene, and nucleotides 16–28 correspond to the 5′ region of CFHR5. The structure of the CFHR gene cluster is presented with the indication of the deleted 24,804-nt-long segment (dashed box). The breakpoint spans from position +8,918 of CFHR2 intron III to –12 in the CFHR5 5′ UTR. Organization of the CFHR2-CFHR5 genes. The exons coding for the signal peptide are in lighter colors and the deleted exons in the CFHR2 gene are indicated by stippled boxes and dashed lines. (C) In serum of both patients, a novel protein doublet with mobilities of 70 and 65 kDa was detected (arrowheads, lanes 2 and 3). In addition, the positions of the 2 CFHR2 isoforms are indicated. Note the lower intensity of CFHR2 in patient sera as compared with NHS. The structures of the hybrid CFHR21,2-CFHR5 protein and CFHR2 are shown. Attached carbohydrates are indicated in black, and, alternatively, attached carbohydrates are indicated in gray.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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