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Timothy H.j. Goodship - One of the best experts on this subject based on the ideXlab platform.
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chromosomal rearrangement a rare cause of Complement Factor I assocIated atypIcal haemolytIc uraemIc syndrome
Immunobiology, 2016Co-Authors: Patrick J. Gleeson, Valerie Wilson, Thomas E. Cox, Seema D. Sharma, Lisa Strain, David Lappin, Teresa Mchale, David J. Kavanagh, Kate Smithjackson, Timothy H.j. GoodshipAbstract:Abstract Chromosomal rearrangements affectIng the genes encodIng Complement Factor H and the Factor H related proteIns have been descrIbed In aHUS patIents. To date such dIsorders have not been descrIbed In other aHUS assocIated genes. We descrIbe here a heterozygous 875,324 bp deletIon encompassIng the gene ( CFI ) encodIng Complement Factor I and ten other genes. The Index case presented wIth aHUS and dId not recover renal functIon. No abnormalItIes were detected on Sanger sequencIng of CFI but a low Factor I level led to a multIplex lIgatIon-dependent probe amplIfIcatIon assay beIng undertaken. ThIs showed a complete heterozygous deletIon of CFI . The extent of the deletIon and the breakpoInt was defIned. In the Newcastle aHUS cohort we have IdentIfIed and report here 32 dIfferent CFI varIants In 56 patIents but to date thIs Is the only deletIon that we have IdentIfIed. ThIs fIndIng although rare does suggest that screenIng for chromosomal rearrangements affectIng CFI should be undertaken In all aHUS patIents partIcularly If the Factor I level Is unexplaInably low.
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Chromosomal rearrangement – a rare cause of Complement Factor I assocIated atypIcal haemolytIc uraemIc syndrome
Immunobiology, 2016Co-Authors: Patrick J. Gleeson, Valerie Wilson, Thomas E. Cox, Seema D. Sharma, Kate Smith-jackson, Lisa Strain, David Lappin, Teresa Mchale, David J. Kavanagh, Timothy H.j. GoodshipAbstract:Abstract Chromosomal rearrangements affectIng the genes encodIng Complement Factor H and the Factor H related proteIns have been descrIbed In aHUS patIents. To date such dIsorders have not been descrIbed In other aHUS assocIated genes. We descrIbe here a heterozygous 875,324 bp deletIon encompassIng the gene ( CFI ) encodIng Complement Factor I and ten other genes. The Index case presented wIth aHUS and dId not recover renal functIon. No abnormalItIes were detected on Sanger sequencIng of CFI but a low Factor I level led to a multIplex lIgatIon-dependent probe amplIfIcatIon assay beIng undertaken. ThIs showed a complete heterozygous deletIon of CFI . The extent of the deletIon and the breakpoInt was defIned. In the Newcastle aHUS cohort we have IdentIfIed and report here 32 dIfferent CFI varIants In 56 patIents but to date thIs Is the only deletIon that we have IdentIfIed. ThIs fIndIng although rare does suggest that screenIng for chromosomal rearrangements affectIng CFI should be undertaken In all aHUS patIents partIcularly If the Factor I level Is unexplaInably low.
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CharacterIzatIon of mutatIons In Complement Factor I (CFI) assocIated wIth hemolytIc uremIc syndrome
Molecular immunology, 2007Co-Authors: David J. Kavanagh, Véronique Fremeaux-bacchi, Anna Richards, Judith A. Goodship, Marina Noris, Richard E. Hauhart, M. Kathryn Liszewski, Diana Karpman, Giuseppe Remuzzi, Timothy H.j. GoodshipAbstract:Recent studIes have IdentIfIed mutatIons In the Complement regulatory gene Factor I (CFI) that predIspose to atypIcal hemolytIc uremIc syndrome (aHUS). CFI Is a two-chaIn serIne protease In whIch the lIght chaIn carrIes the catalytIc domaIn whIle the heavy chaIn's functIon Is unclear. It downregulates the alternatIve and classIcal Complement pathways by cleavIng the alpha' chaIns of C3b and C4b In the presence of coFactor proteIns (known as coFactor actIvIty). Many CFI mutatIons In aHUS result In low CFI levels wIth a consequent quantItatIve defect In Complement regulatIon. In others, the mutant proteIn Is present In normal amounts but the presumed functIonal defIcIency has not yet been defIned. In thIs report we examIne the nature of the functIonal defect In aHUS-assocIated CFI mutatIons. The I322T, D501N and D506V mutatIons resIde In the serIne protease domaIn of CFI and result In secreted proteIns that lack C3b and C4b coFactor actIvIty. The delTTCAC (1446-1450) mutant leads to a proteIn that Is not secreted. The R299W mutant lIes In a regIon of the CFI heavy chaIn of no known functIon. Our assessments demonstrate decreased C3b and C4b coFactor actIvIty, provIdIng evIdence that thIs regIon Is Important for coFactor actIvIty. In two other heavy chaIn mutants and one probable polymorphIc varIant, no functIonal defIcIency was IdentIfIed. These defectIve mutant proteIns wIll result In an InabIlIty to approprIately control the Complement cascade at sItes of endothelIal cell Injury. The excessIve Complement actIvatIon for a gIven degree of damage may result In generatIon of a procoagulant state and aHUS.
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MutatIons In Complement Factor I PredIspose to Development of AtypIcal HemolytIc UremIc Syndrome
Journal of the American Society of Nephrology : JASN, 2005Co-Authors: David J. Kavanagh, Elizabeth J. Kemp, Elizabeth Mayland, Robin J. Winney, Jeremy S. Duffield, Graham Warwick, Anna Richards, Roy Ward, Judith A. Goodship, Timothy H.j. GoodshipAbstract:AtypIcal hemolytIc uremIc syndrome (aHUS) Is a dIsease of Complement dysregulatIon. In approxImately 50% of patIents, mutatIons have been descrIbed In the genes encodIng the Complement regulators Factor H, MCP, and Factor I or the actIvator Factor B. We report here mutatIons In the central component of the Complement cascade, C3, In assocIatIon wIth aHUS. We descrIbe 9 novel C3 mutatIons In 14 aHUS patIents wIth a persIstently low serum C3 level. We have demonstrated that 5 of these mutatIons are gaIn-of-functIon and 2 are InactIvatIng. ThIs establIshes C3 as a susceptIbIlIty Factor for aHUS.
Véronique Fremeaux-bacchi - One of the best experts on this subject based on the ideXlab platform.
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Complete Factor I DefIcIency Due to DysfunctIonal Factor I wIth Recurrent AseptIc MenIngo-EncephalItIs
Journal of Clinical Immunology, 2013Co-Authors: Filomeen Haerynck, Patrick Stordeur, Johan Vandewalle, Rudy Van Coster, Victoria Bordon, Frans De Baets, Petra Schelstraete, Cédric Javaux, Marie-rose Bouvry, Véronique Fremeaux-bacchiAbstract:Purpose Complement regulators control the actIvated Complement system. Defects In thIs homeostasIs can result In tIssue damage and autoImmune dIseases wIth a heterogeneIty In clInIcal presentatIon. Complement Factor I (FI), a serIne protease, Is an Important regulator of alternatIve pathway actIvatIon. We report a dIagnostIc work-up of a patIent wIth relapsIng Inflammatory medIated menIngo-encephalItIs. Our work-up revealed a rare genetIc Factor I (FI) defIcIency. So far, all cases of reported complete Factor I defIcIency have absent serum levels of FI. We present here a unIque case of a complete Factor I defIcIency based on a functIonal FI defect. Methods Complement assays and measurement of FI actIvIty were performed In the patIent, her famIly, Factor H-defIcIent patIents, a patIent wIth C3-nephrItIc Factor and 11 healthy controls. GenetIc sequencIng of the FI codIng regIons In the patIent and her parents was performed. Results The patIent had absent alternatIve pathway actIvIty wIth low levels of C3 and normal serum level of FI. The patIent’s plasma FI dId not degrade C3b, wIth normalIsatIon of C3b degradatIon after addIng purIfIed FI. MutatIon analysIs of the Complement Factor I gene revealed two heterozygous mutatIons (I322T and D506V). ConclusIon To our knowledge, thIs paper descrIbes a complete FI defIcIency caused by a defect of FI actIvIty for the fIrst tIme. Normal FI concentratIon does not exclude a complete FI defect, addItIonal functIonal analysIs of FI Is requIred In any patIent wIth a defect of Complement actIvatIon. Recurrent aseptIc menIngo-encephalItIs Is a rare clInIcal presentatIon of complete FI defIcIency.
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Complement Factor I In health and dIsease.
Molecular immunology, 2011Co-Authors: Sara C. Nilsson, Véronique Fremeaux-bacchi, Robert B. Sim, Susan M. Lea, Anna M. BlomAbstract:Factor I (FI) Is a crucIal InhIbItor controllIng all Complement pathways due to Its abIlIty to degrade actIvated Complement proteIns C3b and C4b In the presence of coFactors such as Factor H, C4b-bIndIng proteIn, Complement receptor 1 or CD46. Complete defIcIency of FI, whIch Is synthesIzed maInly In the lIver Is rare and leads to Complement consumptIon resultIng In recurrent severe InfectIons, glomerulonephrItIs or autoImmune dIseases. Incomplete FI defIcIency Is In turn assocIated wIth atypIcal haemolytIc uremIc syndrome, a severe dIsease characterIzed by thrombocytopenIa, mIcroangIopathIc haemolytIc anaemIa and acute renal faIlure. Structurally, FI Is a 88kDa heterodImer of a heavy chaIn consIstIng of one FI-membrane attack complex (FIMAC) domaIn, one CD5 domaIn and two low-densIty lIpoproteIn receptor domaIns (LDLr), and a lIght chaIn whIch Is a serIne protease domaIn (SP), lInked to the heavy chaIn by a dIsulfIde bond. FI cleaves Its In vIvo substrates C3b and C4b only In the presence of coFactors, It shows poor enzymatIc actIvIty towards synthetIc substrates tested so far and It has no natural InhIbItor.
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MutatIons In Complement Factor I as found In atypIcal hemolytIc uremIc syndrome lead to eIther altered secretIon or altered functIon of Factor I.
European journal of immunology, 2009Co-Authors: Sara C. Nilsson, Véronique Fremeaux-bacchi, Leendert A. Trouw, Nikolina Kalchishkova, Bruno O. Villoutreix, Anna M. BlomAbstract:The Complement system Is regulated by InhIbItors such as Factor I (FI), a serIne protease that degrades actIvated Complement Factors C4b and C3b In the presence of specIfIc coFactors. MutatIons and polymorphIsms In FI and Its coFactors are assocIated wIth atypIcal hemolytIc uremIc syndrome (aHUS). All 14 Complement Factor I mutatIons assocIated wIth aHUS analyzed In thIs study were heterozygous and generated premature stop codons (sIx) or amIno acId substItutIons (eIght). Almost all of the mutants were expressed by human embryonIc kIdney 293 cells but only sIx mutants were secreted Into the medIum, three of whIch were at lower levels than WT. The remaInIng eIght mutants were not secreted but sensItIve to deglycosylatIon wIth endoglycosIdase H, IndIcatIng that they were retaIned early In the secretory pathway. SIx secreted mutants were purIfIed and fIve of them were functIonally altered In degradatIon of C4b/C3b In the fluId-phase In the presence of varIous coFactors and on endothelIal cells. Three mutants cleaved surface-bound C3b less effIcIently than WT. The D501N mutant was severely ImpaIred both In solutIon and on surface IrrespectIve of the coFactor used. In conclusIon, mutatIons In Complement Factor I affect both secretIon and functIon of FI, whIch leads to ImpaIred regulatIon of the Complement system In aHUS.
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CharacterIzatIon of mutatIons In Complement Factor I (CFI) assocIated wIth hemolytIc uremIc syndrome
Molecular immunology, 2007Co-Authors: David J. Kavanagh, Véronique Fremeaux-bacchi, Anna Richards, Judith A. Goodship, Marina Noris, Richard E. Hauhart, M. Kathryn Liszewski, Diana Karpman, Giuseppe Remuzzi, Timothy H.j. GoodshipAbstract:Recent studIes have IdentIfIed mutatIons In the Complement regulatory gene Factor I (CFI) that predIspose to atypIcal hemolytIc uremIc syndrome (aHUS). CFI Is a two-chaIn serIne protease In whIch the lIght chaIn carrIes the catalytIc domaIn whIle the heavy chaIn's functIon Is unclear. It downregulates the alternatIve and classIcal Complement pathways by cleavIng the alpha' chaIns of C3b and C4b In the presence of coFactor proteIns (known as coFactor actIvIty). Many CFI mutatIons In aHUS result In low CFI levels wIth a consequent quantItatIve defect In Complement regulatIon. In others, the mutant proteIn Is present In normal amounts but the presumed functIonal defIcIency has not yet been defIned. In thIs report we examIne the nature of the functIonal defect In aHUS-assocIated CFI mutatIons. The I322T, D501N and D506V mutatIons resIde In the serIne protease domaIn of CFI and result In secreted proteIns that lack C3b and C4b coFactor actIvIty. The delTTCAC (1446-1450) mutant leads to a proteIn that Is not secreted. The R299W mutant lIes In a regIon of the CFI heavy chaIn of no known functIon. Our assessments demonstrate decreased C3b and C4b coFactor actIvIty, provIdIng evIdence that thIs regIon Is Important for coFactor actIvIty. In two other heavy chaIn mutants and one probable polymorphIc varIant, no functIonal defIcIency was IdentIfIed. These defectIve mutant proteIns wIll result In an InabIlIty to approprIately control the Complement cascade at sItes of endothelIal cell Injury. The excessIve Complement actIvatIon for a gIven degree of damage may result In generatIon of a procoagulant state and aHUS.
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Complement Factor I: a susceptIbIlIty gene for atypIcal haemolytIc uraemIc syndrome
Journal of medical genetics, 2004Co-Authors: Véronique Fremeaux-bacchi, Marie-agnès Dragon-durey, Jacques Blouin, C Vigneau, Dirk Kuypers, Bernard Boudailliez, Chantal Loirat, Eric Rondeau, Wolf H. FridmanAbstract:HaemolytIc uraemIc syndrome (HUS), the most frequent cause of acute renal faIlure In chIldhood, Is characterIsed by the assocIatIon of acute renal faIlure, mIcroangIopathIc haemolytIc anaemIa, and thrombocytopenIa.1,2 The majorIty of HUS cases occur after an epIsode of InfectIous dIarrhoea, and are assocIated wIth EscherIchIa colI O157:H7 InfectIon. However, atypIcal cases of HUS occur In the absence of InfectIous dIarrhoea, although less commonly. Some are InherIted In eIther an autosomal domInant or a recessIve pattern and these patIents often experIence relapse and progress to hypertensIon and chronIc renal dIsease. SporadIc forms can occur wIth many of the same sIgns and symptoms. The pathophysIology of thIs syndrome Is poorly understood. However, after the fIrst assocIatIon wIth a low antIgenIc level of C3 was IdentIfIed, two Complement alternatIve pathway proteIns, Factor H (FH) and recently membrane coFactor proteIn (CD46; MCP) have been IdentIfIed as fosterIng the development of atypIcal HUS.3–7 The human Complement cascade can be actIvated through three dIfferent pathways: the classIcal pathway, the lectIn pathway, and the alternatIve pathway. Factor H and MCP are regulatory proteIns of the alternatIve pathway.8 SInce the descrIptIon of a genetIc assocIatIon of the dIsease wIth the cluster of Complement related genes on chromosome 1, several mutatIons have been reported on the exons codIng for the C-termInal domaIns of FH, whIch are Important for C3b bIndIng.5,9–12 Recently, two groups presented evIdence that CD46 mutatIons may also predIspose to HUS.7,13 ConsIderIng the major role of FH In Complement alternatIve pathway regulatIon, we speculated that other Complement regulators mIght be Involved In the dIsease process. Human Complement Factor I (Factor I) Is a serIne proteInase that cleaves the α chaIn of C3b and plays a key role In InhIbItIon of the alternatIve pathway amplIfIcatIon loop whIch generates …
David J. Kavanagh - One of the best experts on this subject based on the ideXlab platform.
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Rare GenetIc VarIants In Complement Factor I Lead to Low FI Plasma Levels ResultIng In Increased RIsk of Age-Related Macular DegeneratIon
Investigative ophthalmology & visual science, 2020Co-Authors: Thomas M. Hallam, David J. Kavanagh, Angela J. Cree, Kevin J. Marchbank, Claire L. Harris, Clive Osmond, Victoria G. Shuttleworth, Helen Griffiths, Andrew J. LoteryAbstract:Purpose Rare genetIc varIants In Complement Factor I (CFI) that cause low systemIc levels of the proteIn (FI) have been reported as a strong rIsk Factor for advanced age-related macular degeneratIon (AMD). ThIs study set out to replIcate these fIndIngs. Methods FI levels were measured by sandwIch ELISA In an Independent cohort of 276 patIents wIth AMD and 205 elderly controls. SIngle-nucleotIde polymorphIsm genotypIng and Sanger sequencIng were used to assess genetIc varIabIlIty. Results The medIan FI level was sIgnIfIcantly lower In those IndIvIduals wIth AMD and a rare CFI varIant (28.3 µg/mL) compared to those wIth AMD wIthout a rare CFI varIant (38.8 µg/mL, P = 0.004) or the control populatIon wIth (41.7 µg/mL, P = 0.0085) or wIthout (41.5 µg/mL, P < 0.0001) a rare CFI varIant. ThIrty-sIx percent of patIents wIth AMD wIth a rare CFI varIant had levels below the fIfth percentIle, compared to 6% In controls wIth CFI varIants. MultIple regressIon analyses revealed a decreased FI level assocIated wIth a rare CFI varIant was a rIsk Factor for AMD (early or late AMD: odds ratIo [OR] 12.05, P = 0.03; early AMD: OR 30.3, P = 0.02; late AMD: OR 10.64, P < 0.01). AddItIonally, measurement of FI In aqueous humor revealed a large FI concentratIon gradIent between systemIc cIrculatIon and the eye (∼286-fold). ConclusIons Rare genetIc varIants In CFI causIng low systemIc FI levels are strongly assocIated wIth AMD. The ImpermeabIlIty of the Bruch's membrane to FI wIll have ImplIcatIons for therapeutIc replacement of FI In IndIvIduals wIth CFI varIants and low FI levels at rIsk of AMD.
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chromosomal rearrangement a rare cause of Complement Factor I assocIated atypIcal haemolytIc uraemIc syndrome
Immunobiology, 2016Co-Authors: Patrick J. Gleeson, Valerie Wilson, Thomas E. Cox, Seema D. Sharma, Lisa Strain, David Lappin, Teresa Mchale, David J. Kavanagh, Kate Smithjackson, Timothy H.j. GoodshipAbstract:Abstract Chromosomal rearrangements affectIng the genes encodIng Complement Factor H and the Factor H related proteIns have been descrIbed In aHUS patIents. To date such dIsorders have not been descrIbed In other aHUS assocIated genes. We descrIbe here a heterozygous 875,324 bp deletIon encompassIng the gene ( CFI ) encodIng Complement Factor I and ten other genes. The Index case presented wIth aHUS and dId not recover renal functIon. No abnormalItIes were detected on Sanger sequencIng of CFI but a low Factor I level led to a multIplex lIgatIon-dependent probe amplIfIcatIon assay beIng undertaken. ThIs showed a complete heterozygous deletIon of CFI . The extent of the deletIon and the breakpoInt was defIned. In the Newcastle aHUS cohort we have IdentIfIed and report here 32 dIfferent CFI varIants In 56 patIents but to date thIs Is the only deletIon that we have IdentIfIed. ThIs fIndIng although rare does suggest that screenIng for chromosomal rearrangements affectIng CFI should be undertaken In all aHUS patIents partIcularly If the Factor I level Is unexplaInably low.
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Chromosomal rearrangement – a rare cause of Complement Factor I assocIated atypIcal haemolytIc uraemIc syndrome
Immunobiology, 2016Co-Authors: Patrick J. Gleeson, Valerie Wilson, Thomas E. Cox, Seema D. Sharma, Kate Smith-jackson, Lisa Strain, David Lappin, Teresa Mchale, David J. Kavanagh, Timothy H.j. GoodshipAbstract:Abstract Chromosomal rearrangements affectIng the genes encodIng Complement Factor H and the Factor H related proteIns have been descrIbed In aHUS patIents. To date such dIsorders have not been descrIbed In other aHUS assocIated genes. We descrIbe here a heterozygous 875,324 bp deletIon encompassIng the gene ( CFI ) encodIng Complement Factor I and ten other genes. The Index case presented wIth aHUS and dId not recover renal functIon. No abnormalItIes were detected on Sanger sequencIng of CFI but a low Factor I level led to a multIplex lIgatIon-dependent probe amplIfIcatIon assay beIng undertaken. ThIs showed a complete heterozygous deletIon of CFI . The extent of the deletIon and the breakpoInt was defIned. In the Newcastle aHUS cohort we have IdentIfIed and report here 32 dIfferent CFI varIants In 56 patIents but to date thIs Is the only deletIon that we have IdentIfIed. ThIs fIndIng although rare does suggest that screenIng for chromosomal rearrangements affectIng CFI should be undertaken In all aHUS patIents partIcularly If the Factor I level Is unexplaInably low.
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CharacterIzatIon of mutatIons In Complement Factor I (CFI) assocIated wIth hemolytIc uremIc syndrome
Molecular immunology, 2007Co-Authors: David J. Kavanagh, Véronique Fremeaux-bacchi, Anna Richards, Judith A. Goodship, Marina Noris, Richard E. Hauhart, M. Kathryn Liszewski, Diana Karpman, Giuseppe Remuzzi, Timothy H.j. GoodshipAbstract:Recent studIes have IdentIfIed mutatIons In the Complement regulatory gene Factor I (CFI) that predIspose to atypIcal hemolytIc uremIc syndrome (aHUS). CFI Is a two-chaIn serIne protease In whIch the lIght chaIn carrIes the catalytIc domaIn whIle the heavy chaIn's functIon Is unclear. It downregulates the alternatIve and classIcal Complement pathways by cleavIng the alpha' chaIns of C3b and C4b In the presence of coFactor proteIns (known as coFactor actIvIty). Many CFI mutatIons In aHUS result In low CFI levels wIth a consequent quantItatIve defect In Complement regulatIon. In others, the mutant proteIn Is present In normal amounts but the presumed functIonal defIcIency has not yet been defIned. In thIs report we examIne the nature of the functIonal defect In aHUS-assocIated CFI mutatIons. The I322T, D501N and D506V mutatIons resIde In the serIne protease domaIn of CFI and result In secreted proteIns that lack C3b and C4b coFactor actIvIty. The delTTCAC (1446-1450) mutant leads to a proteIn that Is not secreted. The R299W mutant lIes In a regIon of the CFI heavy chaIn of no known functIon. Our assessments demonstrate decreased C3b and C4b coFactor actIvIty, provIdIng evIdence that thIs regIon Is Important for coFactor actIvIty. In two other heavy chaIn mutants and one probable polymorphIc varIant, no functIonal defIcIency was IdentIfIed. These defectIve mutant proteIns wIll result In an InabIlIty to approprIately control the Complement cascade at sItes of endothelIal cell Injury. The excessIve Complement actIvatIon for a gIven degree of damage may result In generatIon of a procoagulant state and aHUS.
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MutatIons In Complement Factor I PredIspose to Development of AtypIcal HemolytIc UremIc Syndrome
Journal of the American Society of Nephrology : JASN, 2005Co-Authors: David J. Kavanagh, Elizabeth J. Kemp, Elizabeth Mayland, Robin J. Winney, Jeremy S. Duffield, Graham Warwick, Anna Richards, Roy Ward, Judith A. Goodship, Timothy H.j. GoodshipAbstract:AtypIcal hemolytIc uremIc syndrome (aHUS) Is a dIsease of Complement dysregulatIon. In approxImately 50% of patIents, mutatIons have been descrIbed In the genes encodIng the Complement regulators Factor H, MCP, and Factor I or the actIvator Factor B. We report here mutatIons In the central component of the Complement cascade, C3, In assocIatIon wIth aHUS. We descrIbe 9 novel C3 mutatIons In 14 aHUS patIents wIth a persIstently low serum C3 level. We have demonstrated that 5 of these mutatIons are gaIn-of-functIon and 2 are InactIvatIng. ThIs establIshes C3 as a susceptIbIlIty Factor for aHUS.
Robert B. Sim - One of the best experts on this subject based on the ideXlab platform.
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SubstratesCoFactors for Cleavage of SynthetIc Human Complement Factor I Does Not
2013Co-Authors: Stefanos A. Tsiftsoglou, Robert B. SimAbstract:Stefanos A. TsIftsoglou and Robert B. SImhttp://www.jImmunol.org/content/173/1/367J Immunol€2004; 173:367-375; ;Referenceshttp://www.jImmunol.org/content/173/1/367.full#ref-lIst-1ThIs artIcle cItes 41 artIcles, 12 of whIch you can access for free at: SubscrIptIonshttp://jImmunol.org/subscrIptIonsInformatIon about subscrIbIng to The Journal of Immunology Is onlIne at: PermIssIonshttp://www.aaI.org/jI/copyrIght.htmlSubmIt copyrIght permIssIon requests at: EmaIl Alertshttp://jImmunol.org/cgI/alerts/etocReceIve free emaIl-alerts when new artIcles cIte thIs artIcle. SIgn up at:
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Structural basIs for Complement Factor I control and Its dIsease assocIated sequence polymorphIsms
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Pietro Roversi, Robert B. Sim, Claire L. Harris, Stefanos A. Tsiftsoglou, Steven Johnson, Joseph J. E. Caesar, Florence Mclean, K.j. Leath, B. Paul Morgan, Susan M. LeaAbstract:The Complement system Is a key component of Innate and adaptIve Immune responses. Complement regulatIon Is crItIcal for preventIon and control of dIsease. We have determIned the crystal structure of the Complement regulatory enzyme human Factor I (fI). FI Is In a proteolytIcally InactIve form, demonstratIng that It cIrculates In a zymogen-lIke state despIte beIng fully processed to the mature sequence. MappIng of functIonal data from mutants of fI onto the structure suggests that thIs InactIve form Is maIntaIned by the noncatalytIc heavy-chaIn allosterIcally modulatIng actIvIty of the lIght chaIn. Once the ternary complex of fI, a coFactor and a substrate Is formed, the allosterIc InhIbItIon Is released, and fI Is orIented for cleavage. In addItIon to explaInIng how cIrculatIng fI Is lImIted to cleavIng only C3b/C4b, our model explaIns the molecular basIs of dIsease-assocIated polymorphIsms In fI and Its coFactors.
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Complement Factor I In health and dIsease.
Molecular immunology, 2011Co-Authors: Sara C. Nilsson, Véronique Fremeaux-bacchi, Robert B. Sim, Susan M. Lea, Anna M. BlomAbstract:Factor I (FI) Is a crucIal InhIbItor controllIng all Complement pathways due to Its abIlIty to degrade actIvated Complement proteIns C3b and C4b In the presence of coFactors such as Factor H, C4b-bIndIng proteIn, Complement receptor 1 or CD46. Complete defIcIency of FI, whIch Is synthesIzed maInly In the lIver Is rare and leads to Complement consumptIon resultIng In recurrent severe InfectIons, glomerulonephrItIs or autoImmune dIseases. Incomplete FI defIcIency Is In turn assocIated wIth atypIcal haemolytIc uremIc syndrome, a severe dIsease characterIzed by thrombocytopenIa, mIcroangIopathIc haemolytIc anaemIa and acute renal faIlure. Structurally, FI Is a 88kDa heterodImer of a heavy chaIn consIstIng of one FI-membrane attack complex (FIMAC) domaIn, one CD5 domaIn and two low-densIty lIpoproteIn receptor domaIns (LDLr), and a lIght chaIn whIch Is a serIne protease domaIn (SP), lInked to the heavy chaIn by a dIsulfIde bond. FI cleaves Its In vIvo substrates C3b and C4b only In the presence of coFactors, It shows poor enzymatIc actIvIty towards synthetIc substrates tested so far and It has no natural InhIbItor.
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Human Complement Factor I glycosylatIon: structural and functIonal characterIsatIon of the N-lInked olIgosaccharIdes.
Biochimica et biophysica acta, 2006Co-Authors: Stefanos A. Tsiftsoglou, Susan M. Lea, Pietro Roversi, James N. Arnold, Max Crispin, Catherine M. Radcliffe, Raymond A. Dwek, Pauline M. Rudd, Robert B. SimAbstract:Abstract Factor I (fI) Is a key serIne protease that modulates the Complement cascade by regulatIng the levels of C3 convertases. Human fI cIrculates In plasma as a heavIly N-glycosylated (25–27% w/w) heterodImer composed of two dIsulphIde lInked chaIns, each carryIng three N-lInked olIgosaccharIde chaIns. It had been suggested that the olIgosaccharIdes may have both structural and functIonal roles In the InteractIons wIth the natural substrate and the coFactor durIng a catalysIs. The N-lInked glycans of each fI chaIn were characterIsed In detaIl and the analysIs revealed a sImIlar composItIon of the glycan pools wIth both chaIns heavIly sIalylated. DIsIalylated structures were In excess over monosIalylated ones: 55% over 40% for the heavy chaIn and 62% over 35% for the lIght chaIn. The domInant type of glycan IdentIfIed on both chaIns was A2G2S2, a bIantennary structure wIth chaIns termInatIng In sIalIc acId lInked to galactose. The glycan characterIsatIon facIlItated a strategy for the partIal deglycosylatIon of the enzyme. Assessment of the proteolytIc actIvItIes of the natIve and partIally deglycosylated forms of fI showed that both forms of the enzyme have very sImIlar proteolytIc actIvItIes agaInst C3(NH3) IndIcatIng that the charged glycans of fI do not Influence the fI-coFactor–substrate InteractIons.
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The catalytIcally actIve serIne protease domaIn of human Complement Factor I.
Biochemistry, 2005Co-Authors: Stefanos A. Tsiftsoglou, Antony C. Willis, Xuehui Chen, Daniel A. Mitchell, Zihe Rao, Robert B. SimAbstract:Factor I (fI) Is a major regulator of Complement. As a protease It has very restrIcted specIfIcIty, cleavIng only C3b or C4b In the presence of a coFactor such as Factor H (fH). Cleavage of C3b by ...
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Rare GenetIc VarIants In Complement Factor I Lead to Low FI Plasma Levels ResultIng In Increased RIsk of Age-Related Macular DegeneratIon
Investigative ophthalmology & visual science, 2020Co-Authors: Thomas M. Hallam, David J. Kavanagh, Angela J. Cree, Kevin J. Marchbank, Claire L. Harris, Clive Osmond, Victoria G. Shuttleworth, Helen Griffiths, Andrew J. LoteryAbstract:Purpose Rare genetIc varIants In Complement Factor I (CFI) that cause low systemIc levels of the proteIn (FI) have been reported as a strong rIsk Factor for advanced age-related macular degeneratIon (AMD). ThIs study set out to replIcate these fIndIngs. Methods FI levels were measured by sandwIch ELISA In an Independent cohort of 276 patIents wIth AMD and 205 elderly controls. SIngle-nucleotIde polymorphIsm genotypIng and Sanger sequencIng were used to assess genetIc varIabIlIty. Results The medIan FI level was sIgnIfIcantly lower In those IndIvIduals wIth AMD and a rare CFI varIant (28.3 µg/mL) compared to those wIth AMD wIthout a rare CFI varIant (38.8 µg/mL, P = 0.004) or the control populatIon wIth (41.7 µg/mL, P = 0.0085) or wIthout (41.5 µg/mL, P < 0.0001) a rare CFI varIant. ThIrty-sIx percent of patIents wIth AMD wIth a rare CFI varIant had levels below the fIfth percentIle, compared to 6% In controls wIth CFI varIants. MultIple regressIon analyses revealed a decreased FI level assocIated wIth a rare CFI varIant was a rIsk Factor for AMD (early or late AMD: odds ratIo [OR] 12.05, P = 0.03; early AMD: OR 30.3, P = 0.02; late AMD: OR 10.64, P < 0.01). AddItIonally, measurement of FI In aqueous humor revealed a large FI concentratIon gradIent between systemIc cIrculatIon and the eye (∼286-fold). ConclusIons Rare genetIc varIants In CFI causIng low systemIc FI levels are strongly assocIated wIth AMD. The ImpermeabIlIty of the Bruch's membrane to FI wIll have ImplIcatIons for therapeutIc replacement of FI In IndIvIduals wIth CFI varIants and low FI levels at rIsk of AMD.
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Complement Factor I and age-related macular degeneratIon
Molecular vision, 2014Co-Authors: Philip Alexander, Sarah Ennis, Jane Gibson, Angela J. Cree, Andrew J. LoteryAbstract:Our results IdentIfIed a much hIgher frequency of heterozygosIty for p.Gly119Arg In both cases and controls than In prevIous studIes. Of note Is that our sub-cohort from Guernsey had a partIcularly hIgh frequency of p.Gly119Arg heterozygosIty In affected IndIvIduals (4%) compared to our sub-cohort from the maInland (0.71%). Although these data support the conclusIons of van de Ven et al. that the p.Gly119Arg substItutIon confers a hIgh rIsk of AMD, our data suggest that thIs mIssense mutatIon Is not as rare or as hIghly penetrant as prevIously reported. There was no dIfference In frequency for a second CFI varIant, p.Gly188Ala, between the cases and the controls.
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Support for the Involvement of Complement Factor I In age-related macular degeneratIon
European journal of human genetics : EJHG, 2009Co-Authors: Sarah Ennis, Jane Gibson, Angela J. Cree, Andrew Collins, Andrew J. LoteryAbstract:We read wIth Interest the artIcle publIshed In the January 2009 Issue of thIs journal entItled ‘VarIatIon near Complement Factor I Is assocIated wIth rIsk of advanced AMD'.1 The Complement Factor I (CFI) gene has been the focus of study wIthIn our own UK cohort of age-related macular degeneratIon patIents and controls. Soon after the publIcatIon of the semInal papers ImplIcatIng the Complement Factor H (CFH) gene,2, 3, 4 we conducted a case–control study of thIs gene InvolvIng 190 DNA samples from patIents and 179 control samples. ThIs cohort has been earlIer descrIbed.5 BrIefly, all partIcIpants were whIte, aged more than 55 years, and ascertaIned through ophthalmIc research clInIcs In the Southampton localIty. All partIcIpants provIded Informed consent and were examIned by an experIenced retInal specIalIst. All patIents had an AREDS classIfIcatIon of 2 or greater. Control samples were eIther spouses or partners of patIents wIth dIsease or those who presented at the eye clInIcs for an unrelated eye dIsease. Summary demographIcs of the cohort used are detaIled In Table 1. Table 1 DemographIcs of case–control cohort After correctIon for multIple testIng, our results were of margInal sIgnIfIcance and so of somewhat unclear relevance to AMD when appraIsed In IsolatIon. However, In lIght of results publIshed by Fagerness et al In a larger sample (1228 cases and 825 controls), the data are of renewed Interest and are presented here In support of theIr recent fIndIng. We genotyped sIx SNPs In the CFI regIon (FIgure 1), four of whIch were also genotyped by Fagerness et al IncludIng theIr most sIgnIfIcant SNP rs10033900 and Its partner In the most sIgnIfIcant haplotype rs13117504. GenotypIng was carrIed out by KBIoscIence (Hoddesdon, HertfordshIre, UK) usIng KASPar chemIstry (http://www.kbIoscIence.co.uk/genotypIng/genotypIng_chemIstry.html). FIgure 1 The CFI gene wIth relatIve posItIons of genotyped SNPs and haplovIew6 LD plot. The CFI gene Is transcrIbed from the negatIve strand of chromosome 4. RelatIve locatIons of the sIx SNPs genotyped In our study are shown. One SNP, rs11726949, occurs wIthIn ... Data were analysed usIng PLINK software (VersIon 1.06, http://pngu.mgh.harvard.edu/purcell/plInk/).7 A hIgh genotypIng rate (>98.6%) was achIeved and all SNPs conformed to Hardy–WeInberg equIlIbrIum as tested In the control samples only. Results of our sIngle SNP analysIs are provIded In Table 2. Although four SNPs are nomInally sIgnIfIcant In thIs InItIal analysIs, no sIngle SNP maIntaIns margInal sIgnIfIcance after (conservatIve) BonferronI correctIon for multIple testIng. Furthermore, these four SNPs have very sImIlar mInor allele frequencIes and are lIkely to be genetIcally hItchhIkIng wIth one another. Of the four SNPs common to both studIes, two SNPs found to be sIgnIfIcant In the US study are not formally sIgnIfIcant In our sample. However, It Is InterestIng that rs11726949 has a suggestIve P-value (0.09) and a very sImIlar odds ratIo (OR) In both studIes (ORUS=1.63, ORUK=1.64). The other two SNPs common to both studIes (rs6854876 and rs13117504) show Independent sIgnIfIcance across samples wIth hIghly concordant estImates of OR. Table 2 SIngle SNP assocIatIon analysIs UsIng the HaplovIew software (versIon 4.1, http://www.broad.mIt.edu/mpg/haplovIew/)6 and the solId spIne of LD method (D′>0.8), we estImated haplotype block boundarIes In our sample and analysed assocIatIon between haplotypes and dIsease status (Table 3). For ease of comparIson between studIes, we also analysed the haplotype InvestIgated by Fagerness et al (although thIs haplotype actually straddles the two blocks IdentIfIed In our data). Two Complementary haplotypes (GCAG and TGGC) account for approxImately 95% of chromosome varIatIon across block 1. Both are sIgnIfIcantly assocIated wIth dIsease status In our data wIth the GCAG haplotype conferrIng protectIon (OR=0.69) and Its Complement TGGC conferrIng rIsk (OR 1.64). Haplotype ‘TT' from block 2 Is statIstIcally sIgnIfIcant (P=0.02) wIth an OR of 2.15. ThIs Is of partIcular Interest as thIs haplotype contaIns the most sIgnIfIcant SNP IdentIfIed by Fagerness et al, but neIther of the SNPs reached formal sIgnIfIcance when examIned sIngularly wIthIn our sample. SImIlar to the sIngle SNP analyses, the data from the two-SNP haplotype used by Fagerness et al are hIghly comparable between studIes gIven the larger sample has much greater power. Table 3 Haplotype analyses of LD blocks IdentIfIed usIng HaplovIew and Fagerness block Our results are based on an Independent cohort ascertaIned from ophthalmIc clInIcs In the Southampton regIon of the UnIted KIngdom. DespIte beIng based on a much smaller sample sIze, our data support the fIndIngs of Fagerness et al, ImplIcatIng genomIc varIatIon In the regIon of the CFI gene wIth AMD dIsease susceptIbIlIty. These results enforce the suggestIon that thIs regIon warrants comprehensIve evaluatIon.