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Functional Characterization of the Disease-Associated N-Terminal Complement Factor H Mutation W198R

Dysregulation of the complement alternative pathway is involved in the pathogenesis of several diseases, including the kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). In a patient, initially diagnosed with chronic glomerulonephritis, possibly C3G, and who 6 yea...

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Autores principales: Cserhalmi, Marcell, Uzonyi, Barbara, Merle, Nicolas S., Csuka, Dorottya, Meusburger, Edgar, Lhotta, Karl, Prohászka, Zoltán, Józsi, Mihály
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733548/
https://www.ncbi.nlm.nih.gov/pubmed/29321782
http://dx.doi.org/10.3389/fimmu.2017.01800
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author Cserhalmi, Marcell
Uzonyi, Barbara
Merle, Nicolas S.
Csuka, Dorottya
Meusburger, Edgar
Lhotta, Karl
Prohászka, Zoltán
Józsi, Mihály
author_facet Cserhalmi, Marcell
Uzonyi, Barbara
Merle, Nicolas S.
Csuka, Dorottya
Meusburger, Edgar
Lhotta, Karl
Prohászka, Zoltán
Józsi, Mihály
author_sort Cserhalmi, Marcell
collection PubMed
description Dysregulation of the complement alternative pathway is involved in the pathogenesis of several diseases, including the kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). In a patient, initially diagnosed with chronic glomerulonephritis, possibly C3G, and who 6 years later had an episode of aHUS, a heterozygous missense mutation leading to a tryptophan to arginine exchange (W198R) in the factor H (FH) complement control protein (CCP) 3 domain has previously been identified. The aim of this study was to clarify the functional relevance of this mutation. To this end, wild-type (FH1–4(WT)) and mutant (FH1–4(W198R)) CCPs 1–4 of FH were expressed as recombinant proteins. The FH1–4(W198R) mutant showed decreased C3b binding compared with FH1–4(WT). FH1–4(W198R) had reduced cofactor and decay accelerating activity compared with the wild-type protein. Hemolysis assays demonstrated impaired capacity of FH1–4(W198R) to protect rabbit erythrocytes from human complement-mediated lysis, and also to prevent lysis of sheep erythrocytes in human serum induced by a monoclonal antibody binding in FH CCP5 domain, compared with that of FH1–4(WT). Thus, the FH W198R exchange results in impaired complement alternative pathway regulation. The heterozygous nature of this mutation in the index patient may explain the manifestation of two diseases, likely due to different triggers leading to complement dysregulation in plasma or on cell surfaces.
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spelling pubmed-57335482018-01-10 Functional Characterization of the Disease-Associated N-Terminal Complement Factor H Mutation W198R Cserhalmi, Marcell Uzonyi, Barbara Merle, Nicolas S. Csuka, Dorottya Meusburger, Edgar Lhotta, Karl Prohászka, Zoltán Józsi, Mihály Front Immunol Immunology Dysregulation of the complement alternative pathway is involved in the pathogenesis of several diseases, including the kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). In a patient, initially diagnosed with chronic glomerulonephritis, possibly C3G, and who 6 years later had an episode of aHUS, a heterozygous missense mutation leading to a tryptophan to arginine exchange (W198R) in the factor H (FH) complement control protein (CCP) 3 domain has previously been identified. The aim of this study was to clarify the functional relevance of this mutation. To this end, wild-type (FH1–4(WT)) and mutant (FH1–4(W198R)) CCPs 1–4 of FH were expressed as recombinant proteins. The FH1–4(W198R) mutant showed decreased C3b binding compared with FH1–4(WT). FH1–4(W198R) had reduced cofactor and decay accelerating activity compared with the wild-type protein. Hemolysis assays demonstrated impaired capacity of FH1–4(W198R) to protect rabbit erythrocytes from human complement-mediated lysis, and also to prevent lysis of sheep erythrocytes in human serum induced by a monoclonal antibody binding in FH CCP5 domain, compared with that of FH1–4(WT). Thus, the FH W198R exchange results in impaired complement alternative pathway regulation. The heterozygous nature of this mutation in the index patient may explain the manifestation of two diseases, likely due to different triggers leading to complement dysregulation in plasma or on cell surfaces. Frontiers Media S.A. 2017-12-13 /pmc/articles/PMC5733548/ /pubmed/29321782 http://dx.doi.org/10.3389/fimmu.2017.01800 Text en Copyright © 2017 Cserhalmi, Uzonyi, Merle, Csuka, Meusburger, Lhotta, Prohászka and Józsi. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Cserhalmi, Marcell
Uzonyi, Barbara
Merle, Nicolas S.
Csuka, Dorottya
Meusburger, Edgar
Lhotta, Karl
Prohászka, Zoltán
Józsi, Mihály
Functional Characterization of the Disease-Associated N-Terminal Complement Factor H Mutation W198R
title Functional Characterization of the Disease-Associated N-Terminal Complement Factor H Mutation W198R
title_full Functional Characterization of the Disease-Associated N-Terminal Complement Factor H Mutation W198R
title_fullStr Functional Characterization of the Disease-Associated N-Terminal Complement Factor H Mutation W198R
title_full_unstemmed Functional Characterization of the Disease-Associated N-Terminal Complement Factor H Mutation W198R
title_short Functional Characterization of the Disease-Associated N-Terminal Complement Factor H Mutation W198R
title_sort functional characterization of the disease-associated n-terminal complement factor h mutation w198r
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733548/
https://www.ncbi.nlm.nih.gov/pubmed/29321782
http://dx.doi.org/10.3389/fimmu.2017.01800
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