Complement factor H-related hybrid protein deregulates complement in dense deposit disease
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...
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| Veröffentlicht in: | The Journal of clinical investigation 2014-01, Vol.124 (1), p.145-155 |
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| creator | Chen, Qian Wiesener, Michael Eberhardt, Hannes U Hartmann, Andrea Uzonyi, Barbara Kirschfink, Michael Amann, Kerstin Buettner, Maike Goodship, Tim Hugo, Christian Skerka, Christine Zipfel, Peter F |
| description | 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. |
| doi_str_mv | 10.1172/JCI71866 |
| format | Article |
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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.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI71866</identifier><identifier>PMID: 24334459</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Adult ; Base Sequence ; Biology ; Biomedical research ; Biopsy ; Care and treatment ; Child, Preschool ; Chromosome Deletion ; Complement Activation ; Complement C3-C5 Convertases - metabolism ; Complement C3b - metabolism ; Complement C3b Inactivator Proteins - genetics ; Complement C3b Inactivator Proteins - metabolism ; Complement System Proteins - genetics ; Complement System Proteins - metabolism ; Development and progression ; DNA Mutational Analysis ; Enzyme Stability ; Genes ; Genetic aspects ; Genetic variation ; Glomerulonephritis ; Glomerulonephritis, Membranoproliferative - blood ; Glomerulonephritis, Membranoproliferative - genetics ; Glomerulonephritis, Membranoproliferative - therapy ; HEK293 Cells ; Histology ; Humans ; Infections ; Kidney - pathology ; Kidney diseases ; Kidney Failure, Chronic - blood ; Kidney Failure, Chronic - genetics ; Kidney Failure, Chronic - therapy ; Male ; Microscopy ; Mutant Chimeric Proteins - genetics ; Mutant Chimeric Proteins - metabolism ; Natural products ; Patients ; Physiological aspects ; Plasma ; Plasmapheresis ; Protein Binding ; Proteins ; Sequence Deletion ; Studies ; Treatment Outcome ; Young Adult</subject><ispartof>The Journal of clinical investigation, 2014-01, Vol.124 (1), p.145-155</ispartof><rights>COPYRIGHT 2014 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Jan 2014</rights><rights>Copyright © 2014, American Society for Clinical Investigation 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c742t-d8b88883b03d23a3379f1e6c00277cd06b2c810a91dc34a371f2b2074fffcd973</citedby><cites>FETCH-LOGICAL-c742t-d8b88883b03d23a3379f1e6c00277cd06b2c810a91dc34a371f2b2074fffcd973</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871254/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871254/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24334459$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Qian</creatorcontrib><creatorcontrib>Wiesener, Michael</creatorcontrib><creatorcontrib>Eberhardt, Hannes U</creatorcontrib><creatorcontrib>Hartmann, Andrea</creatorcontrib><creatorcontrib>Uzonyi, Barbara</creatorcontrib><creatorcontrib>Kirschfink, Michael</creatorcontrib><creatorcontrib>Amann, Kerstin</creatorcontrib><creatorcontrib>Buettner, Maike</creatorcontrib><creatorcontrib>Goodship, Tim</creatorcontrib><creatorcontrib>Hugo, Christian</creatorcontrib><creatorcontrib>Skerka, Christine</creatorcontrib><creatorcontrib>Zipfel, Peter F</creatorcontrib><title>Complement factor H-related hybrid protein deregulates complement in dense deposit disease</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>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.</description><subject>Adult</subject><subject>Base Sequence</subject><subject>Biology</subject><subject>Biomedical research</subject><subject>Biopsy</subject><subject>Care and treatment</subject><subject>Child, Preschool</subject><subject>Chromosome Deletion</subject><subject>Complement Activation</subject><subject>Complement C3-C5 Convertases - metabolism</subject><subject>Complement C3b - metabolism</subject><subject>Complement C3b Inactivator Proteins - genetics</subject><subject>Complement C3b Inactivator Proteins - metabolism</subject><subject>Complement System Proteins - genetics</subject><subject>Complement System Proteins - metabolism</subject><subject>Development and progression</subject><subject>DNA Mutational Analysis</subject><subject>Enzyme Stability</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic variation</subject><subject>Glomerulonephritis</subject><subject>Glomerulonephritis, Membranoproliferative - blood</subject><subject>Glomerulonephritis, Membranoproliferative - genetics</subject><subject>Glomerulonephritis, Membranoproliferative - therapy</subject><subject>HEK293 Cells</subject><subject>Histology</subject><subject>Humans</subject><subject>Infections</subject><subject>Kidney - pathology</subject><subject>Kidney diseases</subject><subject>Kidney Failure, Chronic - blood</subject><subject>Kidney Failure, Chronic - genetics</subject><subject>Kidney Failure, Chronic - therapy</subject><subject>Male</subject><subject>Microscopy</subject><subject>Mutant Chimeric Proteins - genetics</subject><subject>Mutant Chimeric Proteins - metabolism</subject><subject>Natural products</subject><subject>Patients</subject><subject>Physiological aspects</subject><subject>Plasma</subject><subject>Plasmapheresis</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Sequence Deletion</subject><subject>Studies</subject><subject>Treatment Outcome</subject><subject>Young Adult</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkt-L1DAQx4Mo3noK_gVSEEQfeuZXm_ZFOBb1Vg4O_PXgS0iTaTdH29QkFe-_N6t751b2wQSSkPnMNzOZQegpwWeECPr6w3ojSFWW99CKFEWVV5RV99EKY0ryWrDqBD0K4RpjwnnBH6ITyhlLx3qFvq3dMPUwwBizVunofHaRe-hVBJNtbxpvTTZ5F8GOmQEP3bwzhUz_dfttGQOkdXLBxszYACrAY_SgVX2AJ_v9FH159_bz-iK_vHq_WZ9f5lpwGnNTNVUarMHMUKYYE3VLoNQpeCG0wWVDdUWwqonRjCsmSEsbigVv21ablN0pevNHd5qbAYxOMXnVy8nbQfkb6ZSVS8tot7JzPySrBKEFTwIv9wLefZ8hRDnYoKHv1QhuDpIUlHPCcVkn9Pk_6LWb_ZjSS1Ti6prgA6pTPUg7ti69q3ei8pyVJRG8JGWi8iNUByOkIN0IrU3XC_7sCJ-mgcHqow6vFg6JifAzdmoOQW4-ffx_9urrkn1xwG5B9XEbXD9H68awBPcfq70LwUN7VxSC5a5x5W3jJvTZYRHvwNtOZb8Ah93kOw</recordid><startdate>20140101</startdate><enddate>20140101</enddate><creator>Chen, Qian</creator><creator>Wiesener, Michael</creator><creator>Eberhardt, Hannes U</creator><creator>Hartmann, Andrea</creator><creator>Uzonyi, Barbara</creator><creator>Kirschfink, Michael</creator><creator>Amann, Kerstin</creator><creator>Buettner, Maike</creator><creator>Goodship, Tim</creator><creator>Hugo, Christian</creator><creator>Skerka, Christine</creator><creator>Zipfel, Peter F</creator><general>American Society for Clinical Investigation</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20140101</creationdate><title>Complement factor H-related hybrid protein deregulates complement in dense deposit disease</title><author>Chen, Qian ; Wiesener, Michael ; Eberhardt, Hannes U ; Hartmann, Andrea ; Uzonyi, Barbara ; Kirschfink, Michael ; Amann, Kerstin ; Buettner, Maike ; Goodship, Tim ; Hugo, Christian ; Skerka, Christine ; Zipfel, Peter F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c742t-d8b88883b03d23a3379f1e6c00277cd06b2c810a91dc34a371f2b2074fffcd973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Base Sequence</topic><topic>Biology</topic><topic>Biomedical research</topic><topic>Biopsy</topic><topic>Care and treatment</topic><topic>Child, Preschool</topic><topic>Chromosome Deletion</topic><topic>Complement Activation</topic><topic>Complement C3-C5 Convertases - metabolism</topic><topic>Complement C3b - metabolism</topic><topic>Complement C3b Inactivator Proteins - genetics</topic><topic>Complement C3b Inactivator Proteins - metabolism</topic><topic>Complement System Proteins - genetics</topic><topic>Complement System Proteins - metabolism</topic><topic>Development and progression</topic><topic>DNA Mutational Analysis</topic><topic>Enzyme Stability</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic variation</topic><topic>Glomerulonephritis</topic><topic>Glomerulonephritis, Membranoproliferative - blood</topic><topic>Glomerulonephritis, Membranoproliferative - genetics</topic><topic>Glomerulonephritis, Membranoproliferative - therapy</topic><topic>HEK293 Cells</topic><topic>Histology</topic><topic>Humans</topic><topic>Infections</topic><topic>Kidney - pathology</topic><topic>Kidney diseases</topic><topic>Kidney Failure, Chronic - blood</topic><topic>Kidney Failure, Chronic - genetics</topic><topic>Kidney Failure, Chronic - 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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.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>24334459</pmid><doi>10.1172/JCI71866</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection; Journals@Ovid Complete |
| subjects | Adult Base Sequence Biology Biomedical research Biopsy Care and treatment Child, Preschool Chromosome Deletion Complement Activation Complement C3-C5 Convertases - metabolism Complement C3b - metabolism Complement C3b Inactivator Proteins - genetics Complement C3b Inactivator Proteins - metabolism Complement System Proteins - genetics Complement System Proteins - metabolism Development and progression DNA Mutational Analysis Enzyme Stability Genes Genetic aspects Genetic variation Glomerulonephritis Glomerulonephritis, Membranoproliferative - blood Glomerulonephritis, Membranoproliferative - genetics Glomerulonephritis, Membranoproliferative - therapy HEK293 Cells Histology Humans Infections Kidney - pathology Kidney diseases Kidney Failure, Chronic - blood Kidney Failure, Chronic - genetics Kidney Failure, Chronic - therapy Male Microscopy Mutant Chimeric Proteins - genetics Mutant Chimeric Proteins - metabolism Natural products Patients Physiological aspects Plasma Plasmapheresis Protein Binding Proteins Sequence Deletion Studies Treatment Outcome Young Adult |
| title | Complement factor H-related hybrid protein deregulates complement in dense deposit disease |
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