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John P. Atkinson - One of the best experts on this subject based on the ideXlab platform.
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Chapter 26 – Membrane Cofactor Protein
The Complement FactsBook, 2018Co-Authors: M K Liszewski, John P. AtkinsonAbstract:Since its discovery ∼30 years ago, our knowledge about Membrane Cofactor Protein (MCP; CD46) has expanded beyond its role as a potent complement regulator that is expressed as a family of four isoforms on most cells and that differ in O-glycosylation and cytoplasmic tails. Initially known as a Cofactor for the factor-I-mediated cleavage of C3b and C4b, CD46 functions now include roles as a pathogen magnet, key constituent in human T cell biology, promoter of epithelial cell autophagy and player in reproductive biology. CD46 also is a promising new therapeutic target for xenotransplantation of transgenic CD46-expressing pig organs, for delivery of anti-tumour agents via viruses (especially adenovirus), and for cancer treatment regimens via use of CD46 monoclonal antibodies. Further, since mice primarily express CD46 on spermatozoa and in eye, the Cd46−/− mice may assist CD46 reproductive studies and provide a much needed model to study age-related macular degeneration.
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chapter 26 Membrane Cofactor Protein
The Complement FactsBook (Second Edition), 2018Co-Authors: Kathryn M Liszewski, John P. AtkinsonAbstract:Since its discovery ∼30 years ago, our knowledge about Membrane Cofactor Protein (MCP; CD46) has expanded beyond its role as a potent complement regulator that is expressed as a family of four isoforms on most cells and that differ in O-glycosylation and cytoplasmic tails. Initially known as a Cofactor for the factor-I-mediated cleavage of C3b and C4b, CD46 functions now include roles as a pathogen magnet, key constituent in human T cell biology, promoter of epithelial cell autophagy and player in reproductive biology. CD46 also is a promising new therapeutic target for xenotransplantation of transgenic CD46-expressing pig organs, for delivery of anti-tumour agents via viruses (especially adenovirus), and for cancer treatment regimens via use of CD46 monoclonal antibodies. Further, since mice primarily express CD46 on spermatozoa and in eye, the Cd46−/− mice may assist CD46 reproductive studies and provide a much needed model to study age-related macular degeneration.
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Immunohistochemical demonstration of Membrane Cofactor Protein (MCP) of complement in normal and diseased kidney tissues.
Clinical and experimental immunology, 2008Co-Authors: M Endoh, John P. Atkinson, M Yamashina, H Ohi, K Funahashi, T Ikuno, T Yasugi, Hidechika OkadaAbstract:The immunohistochemically stained Membrane Cofactor Protein of complement (MCP/CD46), one of the complement regulatory Proteins, was up-regulated in some diseased kidney tissues. MCP in diseased kidneys was strongly concentrated along the glomerular capillary walls as well as in the mesangial regions, while MCP in normal kidneys was weakly detected in all glomerular structural cells and in the epithelial cells of tubules. Since the enhanced staining was noted in those areas where depositions of C3b/C3c occurred, ongoing complement reaction might be responsible for the up-regulation of MCP expression. MCP expression may be up-regulated by complement fragments generated during complement activation in glomerulonephritis. Furthermore, anti-MCP staining was stronger in intensity in patients with moderate to massive Proteinuria, indicating that up-regulation of MCP expression could be directly correlated to the kidney damage.
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Membrane Cofactor Protein mutations in atypical hemolytic uremic syndrome ahus fatal stx hus c3 glomerulonephritis and the hellp syndrome
Blood, 2007Co-Authors: Celia J Fang, Kathryn M Liszewski, Timothy H.j. Goodship, Veronique Fremeauxbacchi, Gaia Pianetti, Marina Noris, John P. AtkinsonAbstract:The hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies demonstrate that heterozygous mutations of Membrane Cofactor Protein (MCP;CD46) predispose to atypical HUS (aHUS), which is not associated with exposure to Shiga toxin (Stx). Among the initial 25 MCP mutations in patients with aHUS were 2, R69W and A304V, that were expressed normally and for which no dysfunction was found. The R69W mutation is in complement control Protein module 2, while A304V is in the hydrophobic transMembrane domain. In addition to 3 patients with aHUS, the A304V mutation was identified in 1 patient each with fatal Stx-HUS, the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and glomerulonephritis with C3 deposits. A major goal was to assess if these putative mutations lead to defective complement regulation. Permanent cell lines expressing the mutated Proteins were complement "challenged," and Membrane control of C3 fragment deposition was monitored. Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transMembrane Proteins in situ.
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Membrane Cofactor Protein mutations in atypical hemolytic uremic syndrome ahus fatal stx hus c3 glomerulonephritis and the hellp syndrome
Blood, 2007Co-Authors: Celia J Fang, Kathryn M Liszewski, Timothy H.j. Goodship, Veronique Fremeauxbacchi, Gaia Pianetti, Marina Noris, John P. AtkinsonAbstract:The hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies demonstrate that heterozygous mutations of Membrane Cofactor Protein (MCP;CD46) predispose to atypical HUS (aHUS), which is not associated with exposure to Shiga toxin (Stx). Among the initial 25 MCP mutations in patients with aHUS were 2, R69W and A304V, that were expressed normally and for which no dysfunction was found. The R69W mutation is in complement control Protein module 2, while A304V is in the hydrophobic transMembrane domain. In addition to 3 patients with aHUS, the A304V mutation was identified in 1 patient each with fatal Stx-HUS, the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and glomerulonephritis with C3 deposits. A major goal was to assess if these putative mutations lead to defective complement regulation. Permanent cell lines expressing the mutated Proteins were complement "challenged," and Membrane control of C3 fragment deposition was monitored. Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transMembrane Proteins in situ.
Kathryn M Liszewski - One of the best experts on this subject based on the ideXlab platform.
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chapter 26 Membrane Cofactor Protein
The Complement FactsBook (Second Edition), 2018Co-Authors: Kathryn M Liszewski, John P. AtkinsonAbstract:Since its discovery ∼30 years ago, our knowledge about Membrane Cofactor Protein (MCP; CD46) has expanded beyond its role as a potent complement regulator that is expressed as a family of four isoforms on most cells and that differ in O-glycosylation and cytoplasmic tails. Initially known as a Cofactor for the factor-I-mediated cleavage of C3b and C4b, CD46 functions now include roles as a pathogen magnet, key constituent in human T cell biology, promoter of epithelial cell autophagy and player in reproductive biology. CD46 also is a promising new therapeutic target for xenotransplantation of transgenic CD46-expressing pig organs, for delivery of anti-tumour agents via viruses (especially adenovirus), and for cancer treatment regimens via use of CD46 monoclonal antibodies. Further, since mice primarily express CD46 on spermatozoa and in eye, the Cd46−/− mice may assist CD46 reproductive studies and provide a much needed model to study age-related macular degeneration.
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Membrane Cofactor Protein mutations in atypical hemolytic uremic syndrome ahus fatal stx hus c3 glomerulonephritis and the hellp syndrome
Blood, 2007Co-Authors: Celia J Fang, Kathryn M Liszewski, Timothy H.j. Goodship, Veronique Fremeauxbacchi, Gaia Pianetti, Marina Noris, John P. AtkinsonAbstract:The hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies demonstrate that heterozygous mutations of Membrane Cofactor Protein (MCP;CD46) predispose to atypical HUS (aHUS), which is not associated with exposure to Shiga toxin (Stx). Among the initial 25 MCP mutations in patients with aHUS were 2, R69W and A304V, that were expressed normally and for which no dysfunction was found. The R69W mutation is in complement control Protein module 2, while A304V is in the hydrophobic transMembrane domain. In addition to 3 patients with aHUS, the A304V mutation was identified in 1 patient each with fatal Stx-HUS, the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and glomerulonephritis with C3 deposits. A major goal was to assess if these putative mutations lead to defective complement regulation. Permanent cell lines expressing the mutated Proteins were complement "challenged," and Membrane control of C3 fragment deposition was monitored. Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transMembrane Proteins in situ.
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Membrane Cofactor Protein mutations in atypical hemolytic uremic syndrome ahus fatal stx hus c3 glomerulonephritis and the hellp syndrome
Blood, 2007Co-Authors: Celia J Fang, Kathryn M Liszewski, Timothy H.j. Goodship, Veronique Fremeauxbacchi, Gaia Pianetti, Marina Noris, John P. AtkinsonAbstract:The hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies demonstrate that heterozygous mutations of Membrane Cofactor Protein (MCP;CD46) predispose to atypical HUS (aHUS), which is not associated with exposure to Shiga toxin (Stx). Among the initial 25 MCP mutations in patients with aHUS were 2, R69W and A304V, that were expressed normally and for which no dysfunction was found. The R69W mutation is in complement control Protein module 2, while A304V is in the hydrophobic transMembrane domain. In addition to 3 patients with aHUS, the A304V mutation was identified in 1 patient each with fatal Stx-HUS, the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and glomerulonephritis with C3 deposits. A major goal was to assess if these putative mutations lead to defective complement regulation. Permanent cell lines expressing the mutated Proteins were complement "challenged," and Membrane control of C3 fragment deposition was monitored. Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transMembrane Proteins in situ.
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mutations in human complement regulator Membrane Cofactor Protein cd46 predispose to development of familial hemolytic uremic syndrome
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Anna Richards, Kathryn M Liszewski, Elizabeth J Kemp, Judith A Goodship, A K Lampe, Ronny Decorte, Hamza M Muslumanogglu, Salih Kavukcu, Guido Filler, Yves PirsonAbstract:Membrane Cofactor Protein (MCP; CD46) is a widely expressed transMembrane complement regulator. Like factor H it inhibits complement activation by regulating C3b deposition on targets. Factor H mutations occur in 10–20% of patients with hemolytic uremic syndrome (HUS). We hypothesized that MCP mutations could predispose to HUS, and we sequenced MCP coding exons in affected individuals from 30 families. MCP mutations were detected in affected individuals of three families: a deletion of two amino acids (D237/S238) in family 1 (heterozygous) and a substitution, S206P, in families 2 (heterozygous) and 3 (homozygous). We evaluated Protein expression and function in peripheral blood mononuclear cells from these individuals. An individual with the D237/S238 deletion had reduced MCP levels and ≈50% C3b binding compared with normal controls. Individuals with the S206P change expressed normal quantities of Protein, but demonstrated ≈50% reduction in C3b binding in heterozygotes and complete lack of C3b binding in homozygotes. MCP expression and function was evaluated in transfectants reproducing these mutations. The deletion mutant was retained intracellularly. S206P Protein was expressed on the cell surface but had a reduced ability to prevent complement activation, consistent with its reduced C3b binding and Cofactor activity. This study presents further evidence that complement dysregulation predisposes to development of thrombotic microangiopathy and that screening patients for such defects could provide informed treatment strategies.
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role of Membrane Cofactor Protein cd46 in regulation of c4b and c3b deposited on cells
Journal of Immunology, 2002Co-Authors: Maria Louise Barillalabarca, Kathryn M Liszewski, D Hourcade, John D. Lambris, John P. AtkinsonAbstract:C4b and C3b deposited on host cells undergo limited proteolytic cleavage by regulatory Proteins. Membrane Cofactor Protein (MCP; CD46), factor H, and C4b binding Protein mediate this reaction, known as Cofactor activity, that also requires the plasma serine protease factor I. To explore the roles of the fluid phase regulators vs those expressed on host cells, a model system was used examining complement fragments deposited on cells transfected with human MCP as assessed by FACS and Western blotting. Following incubation with Ab and complement on MCP+ cells, C4b was progressively cleaved over the first hour to C4d and C4c. There was no detectable cleavage of C4b on MCP− cells, indicating that MCP (and not C4BP in the serum) primarily mediates this Cofactor activity. C3b deposition was not blocked on MCP+ cells because classical pathway activation occurred before substantial C4b cleavage. Cleavage, though, of deposited C3b was rapid (<5 min) and iC3b was the dominant fragment on MCP− and MCP+ cells. Studies using a function-blocking mAb further established factor H as the responsible Cofactor. If the level of Ab sensitization was reduced 8-fold or if Mg2+-EGTA was used to block the classical pathway, MCP efficiently inhibited C3b deposition mediated by the alternative pathway. Thus, for the classical pathway, MCP is the Cofactor for C4b cleavage and factor H for C3b cleavage. However, if the alternative pathway mediates C3b deposition, then MCP’s Cofactor activity is sufficient to restrict complement activation.
Veronique Fremeauxbacchi - One of the best experts on this subject based on the ideXlab platform.
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Membrane Cofactor Protein mutations in atypical hemolytic uremic syndrome ahus fatal stx hus c3 glomerulonephritis and the hellp syndrome
Blood, 2007Co-Authors: Celia J Fang, Kathryn M Liszewski, Timothy H.j. Goodship, Veronique Fremeauxbacchi, Gaia Pianetti, Marina Noris, John P. AtkinsonAbstract:The hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies demonstrate that heterozygous mutations of Membrane Cofactor Protein (MCP;CD46) predispose to atypical HUS (aHUS), which is not associated with exposure to Shiga toxin (Stx). Among the initial 25 MCP mutations in patients with aHUS were 2, R69W and A304V, that were expressed normally and for which no dysfunction was found. The R69W mutation is in complement control Protein module 2, while A304V is in the hydrophobic transMembrane domain. In addition to 3 patients with aHUS, the A304V mutation was identified in 1 patient each with fatal Stx-HUS, the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and glomerulonephritis with C3 deposits. A major goal was to assess if these putative mutations lead to defective complement regulation. Permanent cell lines expressing the mutated Proteins were complement "challenged," and Membrane control of C3 fragment deposition was monitored. Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transMembrane Proteins in situ.
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Membrane Cofactor Protein mutations in atypical hemolytic uremic syndrome ahus fatal stx hus c3 glomerulonephritis and the hellp syndrome
Blood, 2007Co-Authors: Celia J Fang, Kathryn M Liszewski, Timothy H.j. Goodship, Veronique Fremeauxbacchi, Gaia Pianetti, Marina Noris, John P. AtkinsonAbstract:The hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies demonstrate that heterozygous mutations of Membrane Cofactor Protein (MCP;CD46) predispose to atypical HUS (aHUS), which is not associated with exposure to Shiga toxin (Stx). Among the initial 25 MCP mutations in patients with aHUS were 2, R69W and A304V, that were expressed normally and for which no dysfunction was found. The R69W mutation is in complement control Protein module 2, while A304V is in the hydrophobic transMembrane domain. In addition to 3 patients with aHUS, the A304V mutation was identified in 1 patient each with fatal Stx-HUS, the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and glomerulonephritis with C3 deposits. A major goal was to assess if these putative mutations lead to defective complement regulation. Permanent cell lines expressing the mutated Proteins were complement "challenged," and Membrane control of C3 fragment deposition was monitored. Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transMembrane Proteins in situ.
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unusual clinical severity of complement Membrane Cofactor Protein associated hemolytic uremic syndrome and uniparental isodisomy
American Journal of Kidney Diseases, 2007Co-Authors: Veronique Fremeauxbacchi, Marieagnes Dragondurey, Jacques Blouin, Damien Sanlaville, Soraya Menouer, Michel Fischbach, Michel Vekemans, Wolf H. FridmanAbstract:Atypical hemolytic-uremic syndrome (aHUS; OMIM 235400) is genetically and clinically heterogeneous. Mutations in Membrane Cofactor Protein (MCP; CD46), a widely expressed complement regulator, predispose to recurrent forms of the disease. Patients carrying MCP mutations have a favorable clinical outcome in comparison to those with factor H (CFH) or factor I (IF) mutations, which lead in most cases to end-stage renal failure. We identified 1 patient who presented at 1 year of age with a first episode of aHUS requiring dialysis therapy. After 2 recurrences of the disease, the patient developed end-stage renal failure. No mutation in the CFH and IF genes was found. A novel homozygous mutation (IVS10+2 T→C) in the splice-donor of exon 10 encoding the transMembrane region of the MCP gene was associated with dramatically decreased cell-surface expression of MCP. Because the nucleotide substitution was inherited from the patient's father, but not her mother, a large deletion or uniparental disomy was suspected. Both karyotyping and cytogenetic analysis of chromosome 1q32 were performed, for which MCP maps showed no abnormalities. Subsequent genotype analysis using microsatellite markers spanning chromosome 1 showed that the affected child was homozygous for the entire series of markers tested and that all alleles originated from the father. Complete paternal uniparental isodisomy of chromosome 1 is a novel mechanism resulting in severe deficiency of MCP expression. The outcome of the disease reported here indicates that MCP mutation and complete paternal uniparental disomy of chromosome 1 could have an additive effect in determining the severity of the HUS phenotype.
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genetic and functional analyses of Membrane Cofactor Protein cd46 mutations in atypical hemolytic uremic syndrome
Journal of The American Society of Nephrology, 2006Co-Authors: Veronique Fremeauxbacchi, David J. Kavanagh, Elizabeth A Moulton, Marieagnes Dragondurey, Jacques Blouin, Amy A Caudy, Nadia Arzouk, Roxanna Cleper, Maud Francois, G GuestAbstract:Hemolytic uremic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The non-Shiga toxin-associated HUS (atypical HUS [aHUS]) has been shown to be a disease of complement dysregulation. Mutations in the plasma complement regulators factor H and factor I and the widely expressed Membrane Cofactor Protein (MCP; CD46) have been described recently. This study looked for MCP mutations in a panel of 120 patients with aHUS. In this cohort, approximately 10% of patients with aHUS (11 patients; nine pedigrees) have mutations in MCP. The onset typically was in early childhood. Unlike patients with factor I or factor H mutations, most of the patients do not develop end-stage renal failure after aHUS. The majority of patients have a mutation that causes reduced MCP surface expression. A small proportion expressed normal levels of a dysfunctional Protein. As in other studies, incomplete penetrance is shown, suggesting that MCP is a predisposing factor rather than a direct causal factor. The low level of recurrence of aHUS in transplantation in patients with MCP mutations is confirmed, and the first MCP null individuals are described. This study confirms the association between MCP deficiency and aHUS and further establishes that a deficiency in complement regulation, specifically Cofactor activity, predisposes to severe thrombotic microangiopathy in the renal vasculature.
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the development of atypical haemolytic uraemic syndrome is influenced by susceptibility factors in factor h and Membrane Cofactor Protein evidence from two independent cohorts
Journal of Medical Genetics, 2005Co-Authors: Veronique Fremeauxbacchi, Marieagnes Dragondurey, Elizabeth J Kemp, Judith A Goodship, Lisa Strain, Chantal Loirat, Hongwen Deng, Timothy H.j. GoodshipAbstract:Background: In both familial and sporadic atypical haemolytic-uraemic syndrome (aHUS), mutations have been reported in regulators of the alternative complement pathway including factor H (CFH), Membrane Cofactor Protein (MCP), and the serine protease factor I (IF). A characteristic feature of both MCP and CFH associated HUS is reduced penetrance and variable inheritance; one possible explanation for this is that functional changes in complement Proteins act as modifiers. Objective: To examine single nucleotide polymorphisms in both CFH and MCP genes in two large cohorts of HUS patients (Newcastle and Paris). Results: In both cohorts there was an association with HUS for both CFH and MCP alleles. CFH and MCP haplotypes were also significantly different in HUS patients compared with controls. Conclusions: This study suggests that there are naturally occurring susceptibility factors in CFH and MCP for the development of atypical HUS.
Tsukasa Seya - One of the best experts on this subject based on the ideXlab platform.
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Soluble forms of Membrane Cofactor Protein (CD46, MCP) are present in plasma, tears, and seminal fluid in normal subjects.
Clinical and experimental immunology, 2008Co-Authors: Tomoko Hara, M. Matsumoto, S. Kuriyama, H. Kiyohara, Y. Nagase, Tsukasa SeyaAbstract:We have established an ELISA for determination of Membrane Cofactor Protein (MCP, CD46) both solubilized from cell Membranes and released in body fluids. In this assay, mouse MoAbs against MCP, M177 and M160 whose epitopes were different, were used as capture and detection antibodies, respectively. The NP-40 concentration in samples for MCP to be measured must be less than 0.05%. The detection limit of this MCP assay was 0.5 ng. The assay was used to quantify solubilized Membrane MCP, and soluble MCP in normal human plasma, serum, urine, saliva, tears, and seminal fluid, and culture media of tumour cell lines. Soluble MCP was barely detected in the conditioned media of the cell lines. The levels of sMCP in plasma and serum were 10-60 ng/ml and that in tears, 0-50 ng/ml. Seminal fluid contained about 10-fold more soluble MCP than serum. Soluble MCP was not detectable by this assay in the other body fluids, suggesting that their MCP levels were less than the detection limit, if any.
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Urine Levels of CD46 (Membrane Cofactor Protein) Are Increased in Patients with Glomerular Diseases
Clinical immunology (Orlando Fla.), 2000Co-Authors: Tetsuo Shoji, Nakanishi I, K. Kunitou, Yoshiharu Tsubakihara, Y. Hirooka, Y. Kishi, Michiyo Hatanaka, M. Matsumoto, K. Toyoshima, Tsukasa SeyaAbstract:Soluble Membrane Cofactor Protein (MCP, CD46) has not been detected by conventional ELISA in human urine. Here, we established a highly sensitive assay method for determination of urinary MCP (uMCP) using monoclonal antibody-coated paramagnetic beads. This method enabled us to detect less than 0.05 ng/ml of purified Membrane and recombinant soluble MCP, a sensitivity 10-fold higher than that of conventional ELISA. In normal subjects, the levels of uMCP were
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Human Membrane Cofactor Protein (MCP, CD46): multiple isoforms and functions.
The international journal of biochemistry & cell biology, 1999Co-Authors: Tsukasa Seya, Akiko Hirano, Misako Matsumoto, Midori Nomura, Shigeharu UedaAbstract:Abstract Human Membrane Cofactor Protein (MCP, CD46) is a 45–70 kDa Protein with genetic and tissue-specific heterogeneity, and is expressed on all nucleated cells. MCP consists from N-terminus of 4 short consensus repeats (SCRs), 1–3 serine/threonine-rich (ST) domains, a transMembrane domain (TM) and a cytoplasmic tail (CYT). More than 8 isoforms are generated secondary to alternative splicing due to combinations of various exons encoding the ST, TM and CYT domains. It serves as a Cofactor of serine protease factor I for inactivation of complement C3b and C4b. Its primary role is to protect host cells from homologous complement attack by inactivating C3b/C4b deposited on the Membrane. It also acts as receptors for measles virus (MV), some kinds of bacteria and for a putative ligand on oocytes. MV infection causes temporal host immune suppression, which may appear secondary to signaling events through MCP on macrophages and dendritic cells. These functional properties of human MCP may facilitate xenotransplantation and may be useful in the generation of animal models of measles by creating human MCP-expressing animals.
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The regulation of Membrane Cofactor Protein (CD46) expression by the 3' untranslated region in transgenic mice.
Biochemical and biophysical research communications, 1997Co-Authors: Shuji Miyagawa, Tsukasa Seya, Shoki Mikata, Hironori Tanaka, Masahito Ikawa, Katsuya Kominami, Yoshitake Nishimune, Ryota Shirakura, Masaru OkabeAbstract:Regulation of the Membrane Cofactor Protein (MCP: CD46) was examined. While the expression of MCP in mice carrying MCP(BC2) cDNA with 125 bp of 3' untranslated region (3'UT) was minimal, that in mice carrying MCP cDNA without total 3' UT was evident in many organs. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis clearly showed the presence of mRNA even in transgenic mice with 3' UT, suggesting that the expression was regulated at the post-transcriptional stage. The in vitro expression data of MCP molecules on the stable Chinese hamster ovary (CHO) cell clone corresponded to that in transgenic mice. The first 125 bp downregulated the expression of MCP molecules in combination with not only beta-actin, but also SR alpha, promoter. Also, this region inhibited expression of decay accelerating factor (DAF: CD55) molecules when it was inserted into cDNA of DAF. Furthermore, the first 32 bp of the 3' UT revealed the same downregulation effect as 125 bp on MCP molecules. These findings indicated that the first 125 bp (and the first 32 bp in particular) of 3' UT regulate the expression of MCP molecules in transgenic mice.
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Molecular Cloning of a Complementary DNA for a Membrane Cofactor Protein (MCP, CD46)/Measles Virus Receptor on Vero Cells and Its Functional Characterization
Biological & pharmaceutical bulletin, 1996Co-Authors: Yusuke Murakami, Tsukasa Seya, Mitsue Kurita, Shigeharu NagasawaAbstract:We isolated a 1257-bp cDNA encoding a Membrane Cofactor Protein (MCP, CD46)/measles virus (MV) receptor-like Protein from a cDNA library of Vero cells, in which wild MV strains were established. Vero cells contain MCP mRNA splice products encoding different cytoplasmic tails like human cells. The deduced amino acid sequence of the cDNA was 86% identical to that of human MCP. Vero cell MCP expressed on CHO cells was recognized by monoclonal antibodies against human MCP, and served as a potent MV receptor. In addition, Vero MCP was as effective as human MCP in human factor I-mediated C3b cleavage. Thus, the high MV susceptibility of Vero cells can in part be attributed to an MCP-like molecule that is structurally and functionally similar to human MCP.
Timothy H.j. Goodship - One of the best experts on this subject based on the ideXlab platform.
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Membrane Cofactor Protein mutations in atypical hemolytic uremic syndrome ahus fatal stx hus c3 glomerulonephritis and the hellp syndrome
Blood, 2007Co-Authors: Celia J Fang, Kathryn M Liszewski, Timothy H.j. Goodship, Veronique Fremeauxbacchi, Gaia Pianetti, Marina Noris, John P. AtkinsonAbstract:The hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies demonstrate that heterozygous mutations of Membrane Cofactor Protein (MCP;CD46) predispose to atypical HUS (aHUS), which is not associated with exposure to Shiga toxin (Stx). Among the initial 25 MCP mutations in patients with aHUS were 2, R69W and A304V, that were expressed normally and for which no dysfunction was found. The R69W mutation is in complement control Protein module 2, while A304V is in the hydrophobic transMembrane domain. In addition to 3 patients with aHUS, the A304V mutation was identified in 1 patient each with fatal Stx-HUS, the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and glomerulonephritis with C3 deposits. A major goal was to assess if these putative mutations lead to defective complement regulation. Permanent cell lines expressing the mutated Proteins were complement "challenged," and Membrane control of C3 fragment deposition was monitored. Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transMembrane Proteins in situ.
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Membrane Cofactor Protein mutations in atypical hemolytic uremic syndrome ahus fatal stx hus c3 glomerulonephritis and the hellp syndrome
Blood, 2007Co-Authors: Celia J Fang, Kathryn M Liszewski, Timothy H.j. Goodship, Veronique Fremeauxbacchi, Gaia Pianetti, Marina Noris, John P. AtkinsonAbstract:The hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies demonstrate that heterozygous mutations of Membrane Cofactor Protein (MCP;CD46) predispose to atypical HUS (aHUS), which is not associated with exposure to Shiga toxin (Stx). Among the initial 25 MCP mutations in patients with aHUS were 2, R69W and A304V, that were expressed normally and for which no dysfunction was found. The R69W mutation is in complement control Protein module 2, while A304V is in the hydrophobic transMembrane domain. In addition to 3 patients with aHUS, the A304V mutation was identified in 1 patient each with fatal Stx-HUS, the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and glomerulonephritis with C3 deposits. A major goal was to assess if these putative mutations lead to defective complement regulation. Permanent cell lines expressing the mutated Proteins were complement "challenged," and Membrane control of C3 fragment deposition was monitored. Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transMembrane Proteins in situ.
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Membrane Cofactor Protein and factor I: mutations and transplantation.
Seminars in thrombosis and hemostasis, 2006Co-Authors: David J. Kavanagh, Timothy H.j. GoodshipAbstract:Mutations in the genes for three complement regulators-complement factor H (CFH), Membrane Cofactor Protein (MCP), and factor I (IF)-have now been described in patients with atypical HUS. The functional effects of these mutations have been studied in detail and have been shown to affect secretion, expression, and regulatory function. Genotype-phenotype correlations have shown that the majority of patients with CFH, MCP, and FI mutations develop end-stage renal failure. The outcome of transplantation is poor in patients known to have either a CFH or FI mutation, with approximately 80% of patients losing the graft to recurrent disease within 2 years. In contrast, patients known to have only an MCP mutation have a satisfactory transplantation outcome. This is expected because MCP is a transMembrane regulator and allografts will therefore be protected by wild-type MCP. Combined liver/kidney transplantation for patients known to have a CFH mutation has not been successful to date. There is optimism that in the future, targeted complement inhibitors will be of major therapeutic benefit in this condition.
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the development of atypical haemolytic uraemic syndrome is influenced by susceptibility factors in factor h and Membrane Cofactor Protein evidence from two independent cohorts
Journal of Medical Genetics, 2005Co-Authors: Veronique Fremeauxbacchi, Marieagnes Dragondurey, Elizabeth J Kemp, Judith A Goodship, Lisa Strain, Chantal Loirat, Hongwen Deng, Timothy H.j. GoodshipAbstract:Background: In both familial and sporadic atypical haemolytic-uraemic syndrome (aHUS), mutations have been reported in regulators of the alternative complement pathway including factor H (CFH), Membrane Cofactor Protein (MCP), and the serine protease factor I (IF). A characteristic feature of both MCP and CFH associated HUS is reduced penetrance and variable inheritance; one possible explanation for this is that functional changes in complement Proteins act as modifiers. Objective: To examine single nucleotide polymorphisms in both CFH and MCP genes in two large cohorts of HUS patients (Newcastle and Paris). Results: In both cohorts there was an association with HUS for both CFH and MCP alleles. CFH and MCP haplotypes were also significantly different in HUS patients compared with controls. Conclusions: This study suggests that there are naturally occurring susceptibility factors in CFH and MCP for the development of atypical HUS.