Exploring the role of complement factor H-related protein 5 in complement-mediated kidney disorders  Page description

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Details of project

 
Identifier
116119
Type PD
Principal investigator Csuka, Dorottya
Title in Hungarian A komplement H-faktor-rokon fehérje 5 szerepének feltárása komplement-mediált vesebetegségekben
Title in English Exploring the role of complement factor H-related protein 5 in complement-mediated kidney disorders
Keywords in Hungarian komplement H-faktor-rokon fehérje 5, hemolitikus urémiás szindróma, C3-glomerulopátia, komplementrendszer szabályozási zavarai
Keywords in English complement factor H-related protein 5, hemolytic uremic syndrome, C3-glomerulopathy, dysfunction of complement regulation
Discipline
Biological basis of immunity related disorders (e.g. autoimmunity) (Council of Medical and Biological Sciences)50 %
Public health, health services, environmental and occupational medicine, epidemiology, medical ethics (Council of Medical and Biological Sciences)35 %
Ortelius classification: Rare diseases
Immunology (Council of Medical and Biological Sciences)15 %
Ortelius classification: Immunology
Panel Life Sciences Committee Chairs
Department or equivalent 3rd Dept. of Internal Medicine (Semmelweis University)
Starting date 2016-01-01
Closing date 2018-12-31
Funding (in million HUF) 23.352
FTE (full time equivalent) 2.40
state running project





 

Final report

 
Results in Hungarian
Az aHUS a komplement alternatív út regulációs zavarának következményeként alakul ki, hátterében bizonyos komplement gének mutációit, valamint H-faktor elleni autoantitesteket írtak le. A komplement-mediált vesebetegségek közé tartoznak továbbá a C3-glomerulopátiák (C3GP) is, amelyeket a C3 glomerulusokban való lerakódása jellemez. Közös jellemzője e két betegségcsoportnak, hogy a betegek jelentős hányadában nem tárható fel mutáció az eddig leírt génekben, ezért jelen vizsgálatunkban további, eddig ismeretlen patogenetikai tényezőket (mutációkat, autoantitesteket) kerestünk. Pályázatunk során a bevont aHUS-betegek 16.5%-ában, és a C3GP-betegek 13.2%-ában azonosítottunk feltehetően patogén CFHR5 mutációt, továbbá C3GP-betegekben az alábbi patogén autoantitesteket detektáltuk: C3-nefritikus faktor (22.7%), C4-nefritikus faktor (14.3%), anti-C1q (12.6%), anti-B-faktor (6%), anti-H-faktor (5.1%), anti-C3 (4.3%). Az azonosított CFHR5 mutációk lehetséges hatását in silico módszerekkel prediktáltuk, funkcionális jellemzésük érdekében kifejlesztettünk egy-egy ELISA módszert a CFHR5 szint mérésére, illetve a CFHR5 variánsok C3b-, iC3b-kötő képességének a meghatározására, majd a vizsgálatba bevont betegek mintáiban vizsgáltuk ezen paramétereket. Kollaborációs partnereink segítségével az azonosított CFHR5 G278S és R356H variánsokat rekombinánsan expresszáltuk, melyek funkcionális tesztjeink alapján a vad-típusú fehérjéhez képest eltérő ligand-kötő képességgel rendelkeznek.
Results in English
Atypical hemolytic uremic syndrome is caused by the dysregulation of the alternative complement pathway; low-penetration mutations and autoantibodies against factor H were described in its backround. C3 glomerulopathies also belong to the group of complement-mediated renal disorders but these are characterized by C3 deposition in the glomeruli and the altered regulation of the alternative pathway. Surprisingly, a mutation of disease-associated complement genes cannot be detected in a large percent of aHUS patients, and in an even higher proportion of those with C3 glomerulopathies. Thus, our aim was to explore novel pathogenetic factors (mutations, autoantibodies) in the patients. Our research identified a probably pathogenic CFHR5 mutation in 16.5% of aHUS and in 13.2% of C3GP patients. Furthermore, C3GP patients carried several autoantibodies: C3-nephritic factor (22.7%), C4-nephritic factor (14.3%), anti-C1q (12.6%), anti-factor B (6%), anti-factor H (5.1%), anti-C3 (4.3%). The possible functional effect of the identified CFHR5 mutations was predicted using in silico tools, and we developed ELISA methods in order to measure the plasma level of CFHR5 and to analyze the C3b- or iC3b-binding ability of the different CFHR5 variants. The CFHR5 G278S and R356H variants were recombinantly expressed by our collaborating partners and we showed that these mutants are characterized by an altered ligand-binding ability, compared to the wild-type CFHR5 protein.
Full text https://www.otka-palyazat.hu/download.php?type=zarobeszamolo&projektid=116119
Decision
Yes





 

List of publications

 
Eszter Trojnar, Mihály Józsi, Zsóka Szabó, Marienn Réti, Péter Farkas, Kata Kelen, George S Reusz, Attila J Szabó, Nóra Garam, Bálint Mikes, György Sinkovits, Blanka Mező, Dorottya Csuka, Zoltan Prohászka.: Elevated systemic pentraxin-3 is associated with complement consumption in the acute phase of thrombotic microangiopathies., Frontiers in Immunology, 2019 (accepted for publication on 28 January 2019), 2019
Nóra Garam, Zoltán Prohászka, Ágnes Szilágyi, Christof Aigner, Alice Schmidt, Martina Gaggl, Gere Sunder-Plassmann, Dóra Bajcsi, Jürgen Brunner, Alexandra Dumfarth, Daniel Cejka, Stefan Flaschberger, Hana Flögelova, Ágnes Haris, Ágnes Hartmann, Andreas Heilos, Thomas Mueller, Krisztina Rusai, Klaus Arbeiter, Johannes Hofer, Dániel Jakab, Mária Sinkó, Erika Szigeti, Csaba Bereczki, Viktor Janko, Kata Kelen, György S. Reusz, Attila J. Szabó, Nóra Klenk, Krisztina Kóbor, Nika Kojc, Maarten Knechtelsdorfer, Mario Laganovic, Adrian Catalin Lungu, Anamarija Meglic, Rina Rus, Tanja Kersnik-Levart, Ernesta Macioniene, Marius Miglinas, Anna Pawłowska, Tomasz Stompór, Ludmila Podracka, Michael Rudnicki, Gert Mayer, Romana Rysava, Jana Reiterova, Marijan Saraga, Tomáš Seeman, Jakub Zieg, Eva Sládková, Tamás Szabó, Andrei Capitanescu, Simona Stancu, Miroslav Tisljar, Kresimir Galesic, András Tislér, Inga Vainumäe, Martin Windpessl, Tomas Zaoral, Galia Zlatanova, Dorottya Csuka.: C4 nephritic factor in patients with Immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy., Frontiers in Immunology, 2019
Gaggl M, Aigner C, Csuka D, Szilágyi Á, Prohászka Z, Kain R, Haninger N, Knechtelsdorfer M, Sunder-Plassmann R, Sunder-Plassmann G, Schmidt A: Maternal and Fetal Outcomes of Pregnancies in Women with Atypical Hemolytic Uremic Syndrome, J AM SOC NEPHROL 29: (3) pp. 1020-1029., 2018
Karolis Azukaitis, Eva Simkova, Abdul Majid, Matthias Galiano, Kerstin Benz, Kerstin Amann, Clemens Bockmeyer, Anuradha Gajjar, Kevin E Myers, Hae Il Cheong, Bärbel Lange-Sperandio, Marie-Therese Jungraithmayr, Véronique Frémeaux-Bacchi, Carsten Bergmann, Csaba Bereczki, Monika Miklasewska, Dorottya Csuka, Zoltán Prohászka, Matthew Sampson, Mathieu Lemaire, Franz Schaefer.: The Phenotypic Spectrum of Nephropathies Associated with Mutations in Diacylglycerol Kinase ε., Journal of the American Society of Nephrology, 2017 Oct;28(10):3066-3075., 2017
Cserhalmi M, Uzonyi B, Merle NS, Csuka D, Meusburgers E, Lhotta K, Prohaszka Z, Jozsi M: Functional Characterization of the Disease-associated N-Terminal complement Factor H Mutation W198R, FRONT IMMUNOL 8: Paper 1800. 10 p. , 2017
Nóra Garam, Zoltán Prohászka, Michael Rudnicki, Christoph Aigner, Adrian Lungu, Jana Reiterova, Tanja Kersnik Levart, Ágnes Haris, Ágnes Hartmann, György Reusz, Kata Kelen, Csaba Bereczki, Dorottya Csuka.: Validation of pathogenic patterns in a novel cohort of patients with membranoproliferative glomerulonephritis (MPGN) by a cluster analysis., Molecular Immunology, Volume 102, October 2018, Page 153, 2018
Andrei Capitanescu, Magda Zarojanu, Lungu Adrian Catalin, Nóra Veszeli, Dorottya Csuka, Nóra Éva Garam, Zoltan Prohaszka, Sergiu Dumitrache.: Complement-Mediated Glomerulonephritis – a Large Spectrum for a Rare Disease., American Society of Nephrology, 2018
Nora Veszeli, Barbara Uzonyi, Nora Garam, Adrian Lungu, Mihály Józsi, Zoltán Prohászka, Dorottya Csuka: Identification of a CFHR3 hybrid protein in a patient with familial form of C3-glomerulonephritis., Molecular Immunology, Volume 102, October 2018, Page 224, 2018
Marcell Cserhalmi, Barbara Uzonyi, Dorottya Csuka, Katalin Uray, Attila Iliás, Zoltán Prohászka, Mihály Józsi: Functional characterization of disease associated variants of human complement factor H-related protein 5., Molecular Immunology, Volume 102, October 2018, Pages 170-171, 2018
Dorottya Csuka, Nóra Garam, Mihály Józsi, Marcell Cserhalmi, Barbara Uzonyi, Michael Rudnicki, Gere Sunder-Plassmann, Alice Schmidt, George S Reusz, Zoltán Prohászka.: Assessment of the C3b- and iC3b-binding ability of CFHR5 variants., Molecular Immunology, Volume 102, October 2018, Page 141, 2018
Susan A. Lagerstedt, Dorottya Csuka, Zoltan Prohaszka, Roshini S. Abraham.: Analysis of Complement Gene Variants In The Clinical Laboratory: Comparison of Next-Generation Sequencing (NGS) and Sanger Methods., Molecular Immunology, Volume 89, September 2017, Page 149, 2017
Dorottya Csuka, Nóra Garam, Ágnes Szilágyi, Mihály Józsi, Michael Rudnicki, Gere Sunder-Plassmann, Alice Schmidt, George S Reusz, Zoltán Prohászka: Identification of CFHR5 variations in patients with atypical hemolytic uremic syndrome or with C3-glomerulopathies., International Complement Workshop, Kanazawa, Japan (4-8 September 2016), 2016
Aino Koskinen, Trojnár Eszter, Csuka Dorottya, Prohászka Zoltán, Sakari Jokiranta: Whole exome sequencing in diagnostics of atypical hemolytic uremic syndrome., MOL IMMUNOL 89: 148-149, 2017
Cserhalmi M, Uzonyi B, Merle NS, Csuka D, Meusburgers E, Lhotta K, Prohaszka Z, Jozsi M: Functional Characterization of the Disease-associated N-Terminal complement Factor H Mutation W198R, FRONT IMMUNOL 8: , 2017
Csuka D, Garam N, Szilagyi A, Jozsi M, Rudnicki M, Sunder-Plassmann G, Schmidt A, Reusz GS, Prohaszka Z: Relationship between CFHR5 and complement parameters in patients suffering from complement-mediated kidney disorders, with or without CFHR5 mutations, MOL IMMUNOL 89: 177, 2017
Gaggl M, Aigner C, Csuka D, Szilágyi Á, Prohászka Z, Kain R, Haninger N, Knechtelsdorfer M, Sunder-Plassmann R, Sunder-Plassmann G, Schmidt A: Maternal and Fetal Outcomes of Pregnancies in Women with Atypical Hemolytic Uremic Syndrome., J AM SOC NEPHROL : , 2017
Garam Nóra, Csuka Dorottya, Kelen Kata, Reusz György, Prohászka Zoltán: Establishment of a method for the detection of C4-nephritic factor, MOL IMMUNOL 89: (Supplement C) 182, 2017
Csuka D, Garam N, Szilagyi A, Jozsi M, Rudnicki M, Sunder-Plassmann G, Schmidt A, Reusz GS, Prohaszka Z: Relationship between CFHR5 and complement parameters in patients suffering from complement-mediated kidney disorders, with or without CFHR5 mutations, MOL IMMUNOL 89: 177, 2017
Garam Nóra, Csuka Dorottya, Kelen Kata, Reusz György, Prohászka Zoltán: Establishment of a method for the detection of C4-nephritic factor, MOL IMMUNOL 89: (Supplement C) 182, 2017
Aino Koskinen, Trojnár Eszter, Csuka Dorottya, Prohászka Zoltán, Sakari Jokiranta: Whole exome sequencing in diagnostics of atypical hemolytic uremic syndrome., MOL IMMUNOL 89: 148-149, 2017
Dorottya Csuka, Nóra Garam, Ágnes Szilágyi, Mihály Józsi, Michael Rudnicki, Gere Sunder-Plassmann, Alice Schmidt, George S Reusz, Zoltán Prohászka: Identification of CFHR5 variations in patients with atypical hemolytic uremic syndrome or with C3-glomerulopathies., Immunobiology 221 (2016) 1131–1225, 2016




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