CFHR Gene Variations Provide Insights in the Pathogenesis of the Kidney Diseases Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

Total Page:16

File Type:pdf, Size:1020Kb

CFHR Gene Variations Provide Insights in the Pathogenesis of the Kidney Diseases Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy REVIEW www.jasn.org CFHR Gene Variations Provide Insights in the Pathogenesis of the Kidney Diseases Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy Peter F. Zipfel ,1,2 Thorsten Wiech,3 Emma D. Stea,1 and Christine Skerka 1 1Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany; 2Institute of Microbiology, Friedrich-Schiller-University, Jena, Germany; and 3Section of Nephropathology, Institute of Pathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany ABSTRACT Sequence and copy number variations in the human CFHR–Factor H gene cluster regulation on endothelial surfaces and comprising the complement genes CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, and fluid-phase regulation remains intact. In Factor H are linked to the human kidney diseases atypical hemolytic uremic syn- C3 glomerulopathy, FHR mutants in the drome (aHUS) and C3 glomerulopathy. Distinct genetic and chromosomal alter- context of intact Factor H and FHL1 (the ations, deletions, or duplications generate hybrid or mutant CFHR genes, as well Factor H–like protein) affect complement as hybrid CFHR–Factor H genes, and alter the FHR and Factor H plasma repertoire. regulation in the fluid phase and on the A clear association between the genetic modifications and the pathologic outcome glomerular surface, and FHR mutants is emerging: CFHR1, CFHR3,andFactor H gene alterations combined with intact with duplicated interaction segments CFHR2, CFHR4,andCFHR5 genes are reported in atypical hemolytic uremic syn- form large oligomers, which deregulate drome. But alterations in each of the five CFHR genes in the context of an intact complement and compete with Factor H Factor H gene are described in C3 glomerulopathy. These genetic modifications for surface binding. Thus, C3 glomerulop- influence complement function and the interplay of the five FHR proteins with each athy develops due to unique CFHR gene other and with Factor H. Understanding how mutant or hybrid FHR proteins, Factor variations in the context of an intact Factor H::FHR hybrid proteins, and altered Factor H, FHR plasma profiles cause pathology H gene. is of high interest for diagnosis and therapy. Here, we summarize how modifica- tions in the CFHR gene cluster described JASN 31: ccc–ccc, 2020. doi: https://doi.org/10.1681/ASN.2019050515 for aHUS and C3 glomerulopathy cause specific FHR mutants and how they affect the FHR plasma repertoire. Thereby, this Sequence and copy number variations in Factor H on the endothelial surface is review will focus on (1) providing an over- the human CFHR gene cluster are linked altered. In C3 glomerulopathy, the FHR view of complement initiation, with the to the kidney disorders atypical hemo- mutants and a modified FHR plasma two central enzymatic levels and the various lyticuremicsyndrome(aHUS)andC3 repertoire apparently affect local com- effector actions; (2) the characteristic glomerulopathy,1–6 and are further- plement regulation, inducing cell pro- more associated with IgA nephropathy liferation and chronic inflammation. fi (IgAN), with a retinal disease, and with To evaluate how alterations in the ve Published online ahead of print. Publication date – infections.5 8 These copy number varia- CFHR genes and the Factor H gene cause available at www.jasn.org. tions are caused by deletions, duplications, different renal pathologies, we here link Presentaddress:Dr.EmmaD.Stea,Nephrology, and insertions of gene or chromosomal the genetic scenarios, the specificFHR Dialysis and Transplantation Unit, Department of segments and generate CFHR::CFHR, variants expressed in plasma, with the Emergency and Organ Transplantation, University ‘ ’ CFHR::Factor H,andFactor H::CFHR glomerular changes in these kidney dis- Aldo Moro, Bari, Italy. hybrid genes or CFHR genes with dupli- eases. We summarize the role of FHR Correspondence: Prof. Peter F. Zipfel, Department cated elements and result in FHR hybrid proteins as emerging complement mod- of Infection Biology, Leibniz Institute for Natural Products Research and Infection Biology, Beutenbergstr 1 fi fl or mutant proteins and alter the FHR and ulators, ampli ers, and in ammatory 11a, Jena D-07745, Thueringen, Germany. Email: Factor H plasma repertoire. One clear dif- modifiers. In aHUS FHR mutants and in [email protected] ference is emerging: in aHUS, ultimately autoimmune aHUS pathogenic Factor Copyright © 2020 by the American Society of the protective complement action of H–binding autoantibodies alter Factor H Nephrology JASN 31: ccc–ccc,2020 ISSN : 1046-6673/3102-ccc 1 REVIEW www.jasn.org morphologic features of the human AP and the convertase (C2bC4bC3b) of Significance Statement kidney disorders aHUS and C3 glomerul- the LP/CP-pathway use C5 as substrate opathy; (3) giving a brief summary on the and generate C5a and C5b. The human CFHR–Factor H gene cluster organization of the human CFHR–Factor Complement action occurs in the encodes the five FHR proteins that are H gene cluster with the Factor H and the fluid phase and on surfaces and multiple emerging complement and immune mod- fi ulators and the two complement regulators ve CFHR genes and on the structure of regulators control activation and the Factor H and FHL1. Genetic and chromo- the encoded FHR proteins; (4) explaining transition from fluid phase to the surface.9 somal alterations in this cluster are associ- how, in aHUS, CFHR gene variations Both C3 convertases form the inflamma- ated with the human kidney diseases generate Factor H::FHR3, Factor H::FHR1, tory anaphylatoxin C3a and the opsonin atypical hemolytic uremic syndrome and and FHR1::Factor H hybrid proteins and C3b. C3b is handled differently on self and C3 glomerulopathy. Various genetic alter- ations result in the expression of mutant how they alter FHR plasma levels; (5)de- nonself surfaces. C3b deposited on intact and altered FHR proteins, or FHR::Factor H scribing which genetic CFHR changes oc- self surfaces is inactivated by complement and Factor H::FHR hybrid proteins. The cur in C3 glomerulopathy; (6) describing proteases which act together with cofac- modified FHR proteins together with an which FHR hybrid or FHR mutant proteins tors, and inactivated iC3b is further pro- altered FHR and Factor H plasma reper- are expressed in this disease; (7) describing cessed to C3dg and C3d. In addition, C3b toire, which often modify complement action in the fluid phase and cause mor- how altered FHR plasma levels result in C3 when deposited to foreign surfaces ini- phologic alteration in the glomerulus, glomerulopathy; (8) summarizing the new tiates the amplification loop that amplifies provide important views on FHR protein insights into the role of the FHR proteins in C3b deposition. The second enzymatic function in the kidney. IgAN,incomplementcontrolanddisease level with the C5 convertase generates pathology; and (9) providing concluding the potent anaphylatoxin C5a and de- that are causative for the two kidney remarks and an outlook for diagnosis, bio- posits C5b, which initiates the pore- diseases, genetic aHUS and C3 glomerul- marker profiling, and therapy. forming terminal complement complex opathy. The morphologic and cellular al- (TCC) (Figure 1A).13,14 Thus, two enzy- terations, which are caused by deregulated matic steps generate different effector com- complement, are summarized in recent COMPLEMENT: INITIATION, pounds (1) in the form of anaphylatoxins excellent reviews.17,18 The morphologic ENZYMATIC LEVELS, AND C3a and C5a that induce inflammation appearance of aHUS in the glomeruli EFFECTOR PATHWAYS and attract host cells; (2)byopsonization and the preglomerular arterioles can be of target surfaces with C3b; and (3)by characterized as thrombotic microangi- Complement is a central homeotic sys- forming the TCC, which generates a pore tem and defective complement causes and damages the target membrane.15,16 opathy. Best understood is primary many human diseases, in particular the An important challenge is to understand complement-mediated endothelial and kidney diseases aHUS and C3 glomerul- complement regulation and the actions of mesangial cell damage due to dysregulation opathy.9,10 In order to link complement existing regulators and new modulators. of the alternative complement cascade on 19 with CFHR gene variations a brief over- Given that FHR proteins are emerging com- the cell surface. Defective complement view of complement, with the three ac- plement modulators and amplifiers, it is of control on endothelial surfaces results in tivation pathways and with two central interest to define at which specificstepofa cell lysis, followed by thrombus forma- enzymatic checkpoints, is presented pathway and at which checkpoints each tion, loss of mesangial cells, and mesan- (Figure 1A). Activation of the alternative FHR protein acts. The different pathologies giolysis as seen in histology (Figure 1C). pathway occurs spontaneously in the caused by the FHR mutants and hybrids, In the chronic or repair phase, the newly fluid phase and propels on target surfaces; i.e., endothelial damage in aHUS and in formed endothelial cells produce new extra- the lectin and the classic pathways are ini- DEAP-HUS (homozygous CFHR1-CFHR3 cellular matrix, leading to double contours tiated on target surfaces by carbohydrates Deficiency and Autoantibody to Factor H of the glomerular basement membrane and antibodies bound to antigens.9–11 Positive), and inflammatory and prolifera- (GBM) thickening.17,18 In contrast, in C3 Upon initiation, two subsequently acting tive action in C3
Recommended publications
  • Modulation of the Alternative Pathway of Complement by Murine Factor H–Related Proteins
    The Journal of Immunology Modulation of the Alternative Pathway of Complement by Murine Factor H–Related Proteins Alexandra H. Antonioli,* Janice White,† Frances Crawford,† Brandon Renner,* Kevin J. Marchbank,‡ Jonathan P. Hannan,* Joshua M. Thurman,* Philippa Marrack,†,x,{ and V. Michael Holers* Factor H (FH) is a key alternative pathway regulator that controls complement activation both in the fluid phase and on specific cell surfaces, thus allowing the innate immune response to discriminate between self and foreign pathogens. However, the interrela- tionships between FH and a group of closely related molecules, designated the FH-related (FHR) proteins, are currently not well understood. Whereas some studies have suggested that human FHR proteins possess complement regulatory abilities, recent studies have shown that FHR proteins are potent deregulators. Furthermore, the roles of the FHR proteins have not been explored in any in vivo models of inflammatory disease. In this study, we report the cloning and expression of recombinant mouse FH and three FHR proteins (FHR proteins A–C). Results from functional assays show that FHR-A and FHR-B proteins antagonize the protective function of FH in sheep erythrocyte hemolytic assays and increase cell-surface C3b deposition on a mouse kidney proximal tubular cell line (TEC) and a human retinal pigment epithelial cell line (ARPE-19). We also report apparent KD values for the binding interaction of mouse C3d with mouse FH (3.85 mM), FHR-A (136 nM), FHR-B (546 nM), and FHR-C (1.04 mM), which directly correlate with results from functional assays. Collectively, our work suggests that similar to their human counterparts, a subset of mouse FHR proteins have an important modulatory role in complement activation.
    [Show full text]
  • Investigation of Modifier Genes Within Copy Number Variations in Rett Syndrome
    See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/51147767 Investigation of modifier genes within copy number variations in Rett syndrome ARTICLE in JOURNAL OF HUMAN GENETICS · MAY 2011 Impact Factor: 2.53 · DOI: 10.1038/jhg.2011.50 · Source: PubMed CITATIONS DOWNLOADS VIEWS 6 89 134 15 AUTHORS, INCLUDING: Dag H Yasui Maria Antonietta Mencarelli University of California, Davis Azienda Ospedaliera Universitaria Senese 30 PUBLICATIONS 1,674 CITATIONS 58 PUBLICATIONS 962 CITATIONS SEE PROFILE SEE PROFILE Francesca Mari Janine M Lasalle Università degli Studi di Siena University of California, Davis 81 PUBLICATIONS 1,658 CITATIONS 98 PUBLICATIONS 3,525 CITATIONS SEE PROFILE SEE PROFILE Available from: Janine M Lasalle Retrieved on: 22 July 2015 Europe PMC Funders Group Author Manuscript J Hum Genet. Author manuscript; available in PMC 2012 January 01. Published in final edited form as: J Hum Genet. 2011 July ; 56(7): 508–515. doi:10.1038/jhg.2011.50. Europe PMC Funders Author Manuscripts Investigation of modifier genes within copy number variations in Rett syndrome Rosangela Artuso1,*, Filomena Tiziana Papa1,*, Elisa Grillo1, Mafalda Mucciolo1, Dag H. Yasui2, Keith W. Dunaway2, Vittoria Disciglio1, Maria Antonietta Mencarelli1, Marzia Pollazzon1, Michele Zappella3, Giuseppe Hayek4, Francesca Mari1, Alessandra Renieri1, Janine M. LaSalle2, and Francesca Ariani1 1 Medical Genetics Section, Biotechnology Department, University of Siena, Italy 2 Medical Microbiology and Immunology, Genome Center, School of Medicine, University of California, Davis, CA, USA 3 Child Neuropsychiatry, Versilia Hospital, Viareggio, Italy 4 Infantile Neuropsychiatry, Siena General Hospital, Italy Abstract MECP2 mutations are responsible for two different phenotypes in females, classical Rett syndrome and the milder Zappella variant (Z-RTT).
    [Show full text]
  • Biomarker Discovery for Chronic Liver Diseases by Multi-Omics
    www.nature.com/scientificreports OPEN Biomarker discovery for chronic liver diseases by multi-omics – a preclinical case study Daniel Veyel1, Kathrin Wenger1, Andre Broermann2, Tom Bretschneider1, Andreas H. Luippold1, Bartlomiej Krawczyk1, Wolfgang Rist 1* & Eric Simon3* Nonalcoholic steatohepatitis (NASH) is a major cause of liver fbrosis with increasing prevalence worldwide. Currently there are no approved drugs available. The development of new therapies is difcult as diagnosis and staging requires biopsies. Consequently, predictive plasma biomarkers would be useful for drug development. Here we present a multi-omics approach to characterize the molecular pathophysiology and to identify new plasma biomarkers in a choline-defcient L-amino acid-defned diet rat NASH model. We analyzed liver samples by RNA-Seq and proteomics, revealing disease relevant signatures and a high correlation between mRNA and protein changes. Comparison to human data showed an overlap of infammatory, metabolic, and developmental pathways. Using proteomics analysis of plasma we identifed mainly secreted proteins that correlate with liver RNA and protein levels. We developed a multi-dimensional attribute ranking approach integrating multi-omics data with liver histology and prior knowledge uncovering known human markers, but also novel candidates. Using regression analysis, we show that the top-ranked markers were highly predictive for fbrosis in our model and hence can serve as preclinical plasma biomarkers. Our approach presented here illustrates the power of multi-omics analyses combined with plasma proteomics and is readily applicable to human biomarker discovery. Nonalcoholic fatty liver disease (NAFLD) is the major liver disease in western countries and is ofen associated with obesity, metabolic syndrome, or type 2 diabetes.
    [Show full text]
  • Complement Factor H Deficiency and Endocapillary Glomerulonephritis Due to Paternal Isodisomy and a Novel Factor H Mutation
    Genes and Immunity (2011) 12, 90–99 & 2011 Macmillan Publishers Limited All rights reserved 1466-4879/11 www.nature.com/gene ORIGINAL ARTICLE Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation L Schejbel1, IM Schmidt2, M Kirchhoff3, CB Andersen4, HV Marquart1, P Zipfel5 and P Garred1 1Department of Clinical Immunology, Laboratory of Molecular Medicine, Rigshospitalet, Copenhagen, Denmark; 2Department of Pediatrics, Rigshospitalet, Copenhagen, Denmark; 3Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark; 4Department of Pathology, Rigshospitalet, Copenhagen, Denmark and 5Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany Complement factor H (CFH) is a regulator of the alternative complement activation pathway. Mutations in the CFH gene are associated with atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II and C3 glomerulonephritis. Here, we report a 6-month-old CFH-deficient child presenting with endocapillary glomerulonephritis rather than membranoproliferative glomerulonephritis (MPGN) or C3 glomerulonephritis. Sequence analyses showed homozygosity for a novel CFH missense mutation (Pro139Ser) associated with severely decreased CFH plasma concentration (o6%) but normal mRNA splicing and expression. The father was heterozygous carrier of the mutation, but the mother was a non-carrier. Thus, a large deletion in the maternal CFH locus or uniparental isodisomy was suspected. Polymorphic markers across chromosome 1 showed homozygosity for the paternal allele in all markers and a lack of the maternal allele in six informative markers. This combined with a comparative genomic hybridization assay demonstrated paternal isodisomy. Uniparental isodisomy increases the risk of homozygous variations in other genes on the affected chromosome.
    [Show full text]
  • New Functional and Structural Insights from Updated Mutational Databases for Complement Factor H, Factor I, Membrane Cofactor Protein and C3
    Biosci. Rep. (2014) / 34 / art:e00146 / doi 10.1042/BSR20140117 New functional and structural insights from updated mutational databases for complement factor H, Factor I, membrane cofactor protein and C3 Elizabeth Rodriguez*1, Pavithra M. Rallapalli*1, Amy J. Osborne* and Stephen J. Perkins*2 *Department of Structural and Molecular Biology, Darwin Building, University College London, Gower Street, London WC1E 6BT, U.K. Synopsis aHUS (atypical haemolytic uraemic syndrome), AMD (age-related macular degeneration) and other diseases are associated with defective AP (alternative pathway) regulation. CFH (complement factor H), CFI (complement factor I), MCP (membrane cofactor protein) and C3 exhibited the most disease-associated genetic alterations in the AP.Our interactive structural database for these was updated with a total of 324 genetic alterations. A consensus structure for the SCR (short complement regulator) domain showed that the majority (37 %) of SCR mutations occurred at its hypervariable loop and its four conserved Cys residues. Mapping 113 missense mutations onto the CFH structure showed that over half occurred in the C-terminal domains SCR-15 to -20. In particular, SCR-20 with the highest total of affected residues is associated with binding to C3d and heparin-like oligosaccharides. No clustering of 49 missense mutations in CFI was seen. In MCP, SCR-3 was the most affected by 23 missense mutations. In C3, the neighbouring thioester and MG (macroglobulin) domains exhibited most of 47 missense mutations. The mutations in the regulators CFH, CFI and MCP involve loss-of-function, whereas those for C3 involve gain-of-function. This combined update emphasizes the importance of the complement AP in inflammatory disease, clarifies the functionally important regions in these proteins, and will facilitate diagnosis and therapy.
    [Show full text]
  • Epistatic Interactions of Genetic Loci Associated with Age-Related
    www.nature.com/scientificreports OPEN Epistatic interactions of genetic loci associated with age‑related macular degeneration Christina Kiel1,3, Christoph A. Nebauer1,3, Tobias Strunz1,3, Simon Stelzl1 & Bernhard H. F. Weber 1,2* The currently largest genome‑wide association study (GWAS) for age‑related macular degeneration (AMD) defnes disease association with genome‑wide signifcance for 52 independent common and rare genetic variants across 34 chromosomal loci. Overall, these loci contain over 7200 variants and are enriched for genes with functions indicating several shared cellular processes. Still, the precise mechanisms leading to AMD pathology are largely unknown. Here, we exploit the phenomenon of epistatic interaction to identify seemingly independent AMD‑associated variants that reveal joint efects on gene expression. We focus on genetic variants associated with lipid metabolism, organization of extracellular structures, and innate immunity, specifcally the complement cascade. Multiple combinations of independent variants were used to generate genetic risk scores allowing gene expression in liver to be compared between low and high‑risk AMD. We identifed genetic variant combinations correlating signifcantly with expression of 26 genes, of which 19 have not been associated with AMD before. This study defnes novel targets and allows prioritizing further functional work into AMD pathobiology. A frst successful genome-wide association study (GWAS) was reported in 2005 and identifed with genome- wide signifcance genetic variants at the CFH locus associated with age-related macular degeneration (AMD), a complex disease which is a frequent cause of progressive vision loss in the elderly population 1. Since then, the list of AMD-associated genetic variation has grown exponentially, presently bringing the total to 52 independent common and rare variants across 34 chromosomal loci2.
    [Show full text]
  • Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways
    biomolecules Article Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways Aayushi Srivastava 1,2,3,4 , Abhishek Kumar 1,5,6 , Sara Giangiobbe 1, Elena Bonora 7, Kari Hemminki 1, Asta Försti 1,2,3 and Obul Reddy Bandapalli 1,2,3,* 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; [email protected] (A.S.); [email protected] (A.K.); [email protected] (S.G.); [email protected] (K.H.); [email protected] (A.F.) 2 Hopp Children’s Cancer Center (KiTZ), D-69120 Heidelberg, Germany 3 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany 4 Medical Faculty, Heidelberg University, D-69120 Heidelberg, Germany 5 Institute of Bioinformatics, International Technology Park, Bangalore 560066, India 6 Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India 7 S.Orsola-Malphigi Hospital, Unit of Medical Genetics, 40138 Bologna, Italy; [email protected] * Correspondence: [email protected]; Tel.: +49-6221-42-1709 Received: 29 August 2019; Accepted: 10 October 2019; Published: 13 October 2019 Abstract: Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family.
    [Show full text]
  • Mai Muudatuntuu Ti on Man Mini
    MAIMUUDATUNTUU US009809854B2 TI ON MAN MINI (12 ) United States Patent ( 10 ) Patent No. : US 9 ,809 ,854 B2 Crow et al. (45 ) Date of Patent : Nov . 7 , 2017 Whitehead et al. (2005 ) Variation in tissue - specific gene expression ( 54 ) BIOMARKERS FOR DISEASE ACTIVITY among natural populations. Genome Biology, 6 :R13 . * AND CLINICAL MANIFESTATIONS Villanueva et al. ( 2011 ) Netting Neutrophils Induce Endothelial SYSTEMIC LUPUS ERYTHEMATOSUS Damage , Infiltrate Tissues, and Expose Immunostimulatory Mol ecules in Systemic Lupus Erythematosus . The Journal of Immunol @(71 ) Applicant: NEW YORK SOCIETY FOR THE ogy , 187 : 538 - 552 . * RUPTURED AND CRIPPLED Bijl et al. (2001 ) Fas expression on peripheral blood lymphocytes in MAINTAINING THE HOSPITAL , systemic lupus erythematosus ( SLE ) : relation to lymphocyte acti vation and disease activity . Lupus, 10 :866 - 872 . * New York , NY (US ) Crow et al . (2003 ) Microarray analysis of gene expression in lupus. Arthritis Research and Therapy , 5 :279 - 287 . * @(72 ) Inventors : Mary K . Crow , New York , NY (US ) ; Baechler et al . ( 2003 ) Interferon - inducible gene expression signa Mikhail Olferiev , Mount Kisco , NY ture in peripheral blood cells of patients with severe lupus . PNAS , (US ) 100 ( 5 ) : 2610 - 2615. * GeneCards database entry for IFIT3 ( obtained from < http : / /www . ( 73 ) Assignee : NEW YORK SOCIETY FOR THE genecards. org /cgi - bin / carddisp .pl ? gene = IFIT3 > on May 26 , 2016 , RUPTURED AND CRIPPLED 15 pages ) . * Navarra et al. (2011 ) Efficacy and safety of belimumab in patients MAINTAINING THE HOSPITAL with active systemic lupus erythematosus : a randomised , placebo FOR SPECIAL SURGERY , New controlled , phase 3 trial . The Lancet , 377 :721 - 731. * York , NY (US ) Abramson et al . ( 1983 ) Arthritis Rheum .
    [Show full text]
  • A Genome-Wide Association Study Identifies Key Modulators of Complement Factor H Binding to Malondialdehyde-Epitopes
    A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes Lejla Alica,b,c,1, Nikolina Papac-Milicevica,b,1,2, Darina Czamarad, Ramona B. Rudnicke, Maria Ozsvar-Kozmaa,b, Andrea Hartmanne, Michael Gurbisza, Gregor Hoermanna,f, Stefanie Haslinger-Huttera, Peter F. Zipfele,g, Christine Skerkae, Elisabeth B. Binderd, and Christoph J. Bindera,b,2 aDepartment of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria; bResearch Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; cDepartment of Medical Biochemistry, Faculty of Medicine, University of Sarajevo, 71000 Sarajevo, Bosnia and Herzegovina; dDepartment of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany; eDepartment of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany; fCentral Institute for Medical and Chemical Laboratory Diagnosis, University Hospital Innsbruck, 6020 Innsbruck, Austria; and gInstitute for Microbiology, Friedrich Schiller University, 07743 Jena, Germany Edited by Thaddeus Dryja, Harvard Medical School, Boston, MA, and approved March 17, 2020 (received for review August 12, 2019) Genetic variants within complement factor H (CFH), a major head-to-tail fashion. Moreover, its splice variant factor H-like alternative complement pathway regulator, are associated with protein 1 (FHL-1), consisting of the first seven SCRs of CFH, the development of age-related
    [Show full text]
  • A Hybrid CFHR3-1 Gene Causes Familial C3 Glomerulopathy
    BRIEF COMMUNICATION www.jasn.org A Hybrid CFHR3-1 Gene Causes Familial C3 Glomerulopathy †‡ Talat H. Malik,* Peter J. Lavin, Elena Goicoechea de Jorge,* Katherine A. Vernon,* | Kirsten L. Rose,* Mitali P. Patel,* Marcel de Leeuw,§ John J. Neary, Peter J. Conlon,¶ † Michelle P. Winn, and Matthew C. Pickering* *Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom; †Department of Medicine, Duke University Medical Center, Durham, North Carolina; ‡Trinity Health Kidney Centre, Tallaght Hospital, Trinity College, Dublin, Ireland; §Beckman Coulter Genomics, Grenoble, France; |Department of Renal Medicine, Royal Infirmary Edinburgh, Edinburgh, United Kingdom; and ¶Department of Nephrology, Beaumont Hospital, Dublin, Ireland ABSTRACT Controlled activation of the complement system, a key component of innate immunity, that CFHR1 and CFHR3 impair comple- enables destruction of pathogens with minimal damage to host tissue. Complement ment processing within the kidney. This factor H (CFH), which inhibits complement activation, and five CFH-related proteins hypothesis would predict that an increase (CFHR1–5) compose a family of structurally related molecules. Combined deletion of in CFHR1 and CFHR3 copy number would CFHR3 and CFHR1 is common and confers a protective effect in IgA nephropathy. Here, enhance susceptibility to complement- we report an autosomal dominant complement-mediated GN associated with abnormal mediated kidney injury. Here, we report increases in copy number across the CFHR3 and CFHR1 loci. In addition to normal a novel CFHR3–1 hybrid gene located on copies of these genes, affected individuals carry a unique hybrid CFHR3–1 gene. an allele that also contained intact copies In addition to identifying an association between these genetic observations and of the CFHR1 and CFHR3 genes.
    [Show full text]
  • Complement System in the Pathogenesis of Benign Lymphoepithelial Lesions of the Lacrimal Gland
    RESEARCH ARTICLE Complement System in the Pathogenesis of Benign Lymphoepithelial Lesions of the Lacrimal Gland Jing Li1,2, Xin Ge1, Xiaona Wang1,2, Xiao Liu1, Jianmin Ma1* 1 Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing, China, 2 Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China * [email protected] Abstract Objective We aimed to examine the potential involvement of local complement system gene expres- sion in the pathogenesis of benign lymphoepithelial lesions (BLEL) of the lacrimal gland. OPEN ACCESS Citation: Li J, Ge X, Wang X, Liu X, Ma J (2016) Methods Complement System in the Pathogenesis of Benign We collected data from 9 consecutive pathologically confirmed patients with BLEL of the Lymphoepithelial Lesions of the Lacrimal Gland. PLoS ONE 11(2): e0148290. doi:10.1371/journal. lacrimal gland and 9 cases with orbital cavernous hemangioma as a control group, and pone.0148290 adopted whole genome microarray to screen complement system-related differential Editor: Qiang WANG, Sichuan University, CHINA genes, followed by RT-PCR verification and in-depth enrichment analysis (Gene Ontology analysis) of the gene sets. Received: September 26, 2015 Accepted: January 15, 2016 Results Published: February 5, 2016 The expression of 14 complement system-related genes in the pathologic tissue, including Copyright: © 2016 Li et al. This is an open access C2, C3, ITGB2, CR2, C1QB, CR1, ITGAX, CFP, C1QA, C4B|C4A, FANCA, C1QC, C3AR1 article distributed under the terms of the Creative and CFHR4, were significantly upregulated while 7 other complement system-related Commons Attribution License, which permits genes, C5, CFI, CFHR1|CFH, CFH, CD55, CR1L and CFD were significantly downregulated unrestricted use, distribution, and reproduction in any medium, provided the original author and source are in the lacrimal glands of BLEL patients.
    [Show full text]
  • The Impact of Complement Genes on the Risk of Late-Onset Alzheimer's
    G C A T T A C G G C A T genes Article The Impact of Complement Genes on the Risk of Late-Onset Alzheimer’s Disease Sarah M. Carpanini 1,2,† , Janet C. Harwood 3,† , Emily Baker 1, Megan Torvell 1,2, The GERAD1 Consortium ‡, Rebecca Sims 3 , Julie Williams 1 and B. Paul Morgan 1,2,* 1 UK Dementia Research Institute at Cardiff University, School of Medicine, Cardiff, CF24 4HQ, UK; [email protected] (S.M.C.); [email protected] (E.B.); [email protected] (M.T.); [email protected] (J.W.) 2 Division of Infection and Immunity, School of Medicine, Systems Immunity Research Institute, Cardiff University, Cardiff, CF14 4XN, UK 3 Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, UK; [email protected] (J.C.H.); [email protected] (R.S.) * Correspondence: [email protected] † These authors contributed equally to this work. ‡ Data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium. As such, the investigators within the GERAD1 consortia contributed to the design and implementation of GERAD1 and/or provided data but did not participate in analysis or writing of this report. A full list of GERAD1 investigators and their affiliations is included in Supplementary File S1. Abstract: Late-onset Alzheimer’s disease (LOAD), the most common cause of dementia, and a huge global health challenge, is a neurodegenerative disease of uncertain aetiology. To deliver Citation: Carpanini, S.M.; Harwood, effective diagnostics and therapeutics, understanding the molecular basis of the disease is essential.
    [Show full text]