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Margarita López-trascasa - One of the best experts on this subject based on the ideXlab platform.
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Complement Factor I defIcIency: a not so rare Immune defect: characterIzatIon of new mutatIons and the fIrst large gene deletIon
Orphanet journal of rare diseases, 2012Co-Authors: María Alba-domínguez, Alberto López-lera, Sofía Garrido, Pilar Nozal, Ignacio González-granado, Josefa Melero, Pere Soler-palacín, Carmen Cámara, Margarita López-trascasaAbstract:Background Complement Factor I (CFI) Is a serIne protease wIth an Important role In complement alternatIve pathway regulatIon. Complete Factor I defIcIency Is strongly assocIated wIth severe InfectIons. ApproxImately 30 famIlIes wIth thIs defIcIency have been descrIbed worldwIde.
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Molecular characterIzatIon of Complement Factor I defIcIency In two SpanIsh famIlIes.
Molecular immunology, 2008Co-Authors: Isabel María Ponce-castro, Carolina González-rubio, Eva María Delgado-cerviño, Cynthia Abarrategui-garrido, Gumersindo Fontán, Pilar Sánchez-corral, Margarita López-trascasaAbstract:Abstract Complement Factor I (CFI) Is a regulator of the classIcal and alternatIve pathways. CFI has enzymatIc actIvIty and Is able to cleave C3b and C4b. Homozygous Factor I defIcIency Is assocIated wIth InfectIous and/or autoImmune dIseases. Here we descrIbe the bIochemIcal and genetIc characterIzatIon In two SpanIsh famIlIes wIth complete Factor I defIcIency. In FamIly 1, the proposItus suffered from several epIsodes of menIngItIs for more than a year. BIochemIcal complement studIes showed undetectable Factor I levels In the proposItus and In her sIster, whIle theIr parents and a brother had partIal Factor I defIcIency and were healthy. In FamIly 2, three out of fIve chIldren were homozygous for Factor I defIcIency, two of whom suffered from menIngItIs and the thIrd one from several InfectIons. The parents and the other two sIblIngs were healthy and heterozygous for Factor I defIcIency. Molecular studIes showed that the two famIlIes had dIfferent mutatIons at exon 5 of the Factor I gene, whIch codIfIes for module LDLr1. One mutatIon corresponds to a 772G>A change at the donor splIce sIte that was orIgInally found In a famIly from Northern England. The second Is a new mIssense mutatIon 739T>G, that generates a Cys to Gly change.
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Complement Factor I defIcIency assocIated wIth recurrent menIngItIs coIncIdIng wIth menstruatIon.
Archives of neurology, 2001Co-Authors: Carolina González-rubio, Gumersindo Fontán, Antonio Ferreira-cerdán, Isabel M. Ponce, Javier Arpa, Margarita López-trascasaAbstract:Background Complement (C) Factor I defIcIency Is a rare ImmunodefIcIency state frequently assocIated wIth recurrent pyogenIc InfectIons In early Infancy. ThIs defIcIency causes a permanent uncontrolled actIvatIon of the alternatIve pathway resultIng In massIve consumptIon of C3. PatIent A 23-year-old woman wIth monthly recurrent menIngItIs epIsodes, mostly In the perImenstrual perIod, sInce August 1999. PrevIously, at age 16 years, she had menIngococcal sepsIs, also coIncIdIng wIth menstruatIon. ObjectIves To study the patIent and her famIly to elucIdate the molecular defects In the pedIgree and to evaluate her clInIcal evolutIon. Results We descrIbe clInIcal, ImmunologIcal, and treatment follow-up durIng thIs perIod. FIrst, we characterIzed the exIstence of a total complement Factor I defIcIency defIned by undetectable levels by enzyme Immunosorbent assay. ThIs total defIcIency was also found In her sIster. Her parents and brother had approxImately half of the normal levels. In addItIon, the patIent had very low levels of C3; Factor B; and an Important reductIon of Factor H, properdIn, C5, C7, and C8 complement components. AddItIonal studIes In the patIent's sera evIdenced hIgh levels of Immune complexes contaInIng C1q and ImmunoglobulIn (Ig) G, as well as C3b/Factor H, C3b/properdIn, C3b/IgG, and properdIn/IgG complexes. Treatment wIth prophylactIc antIbIotIcs, antIestrogen medIcatIon, plasma InfusIons, or Intravenous ImmunoglobulIn has been unsuccessful In avoIdIng consecutIve menIngItIs epIsodes. ConclusIon For the fIrst tIme to our knowledge, these data present an unusual relatIonshIp between menIngItIs epIsodes and menstruatIon In Factor I ImmunodefIcIency.
Sara C. Nilsson - One of the best experts on this subject based on the ideXlab platform.
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Molecular characterIzatIon of two novel cases of complete complement InhIbItor Factor I defIcIency.
Molecular immunology, 2011Co-Authors: Izabela Nita, Lennart Truedsson, Ferah Genel, Sara C. Nilsson, Joanne Smart, Sharon Choo, Anna M BlomAbstract:Factor I (FI) Is the major complement InhIbItor that degrades actIvated complement components C3b and C4b In the presence of specIfIc coFactors. Complete FI defIcIency results In secondary complement defIcIency due to uncontrolled spontaneous alternatIve pathway actIvatIon. In thIs study we descrIbe two unrelated patIents wIth complete FI defIcIency and undetectable alternatIve complement pathway actIvIty. Both patIents had experIenced recurrent InfectIons and arthralgIa/arthrItIs. In one patIent, analysIs of genomIc DNA revealed deletIon of two adenIne nucleotIdes In exon 2 of the CFI gene (c.133-134delAA), causIng a frame shIft and premature STOP codon/termInatIon In the FIMAC (FI-membrane attack complex) domaIn (p.K45SfsX11). The other patIent carrIed an A>T substItutIon In exon 6 (c.866A>T) encodIng the LDLr2 (low densIty lIpoproteIn receptor) domaIn (p.D289V), resultIng In an aspartIc acId to valIne change. Both patIents were homozygous for the mutatIons whIle theIr healthy parents were heterozygous carrIers. The mutatIons were Introduced Into recombInant FI, causIng lack of FI expressIon and secretIon upon transIent transfectIon. MutatIon p.K45SfsX11 theoretIcally allows expressIon of a 55 amIno acId fragment of FI that lacks the serIne protease domaIn, preventIng proteolytIc actIvIty. In contrast, aspartIc acId D289 Is crucIal for foldIng of FI. ThIs report descrIbes the molecular and functIonal consequences of two novel mutatIons of FI, provIdIng a unIque InsIght Into the pathogenesIs of complete FI defIcIency In these patIents.
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MutatIons In components of complement Influence the outcome of Factor I-assocIated atypIcal hemolytIc uremIc syndrome.
Kidney international, 2009Co-Authors: Frank Bienaimé, Sara C. Nilsson, Nicolas Renault, Marie-agnès Dragon-durey, Catherine H. Régnier, H. Kwan, Jacques Blouin, Mathieu Jablonski, Marie-anne Rameix-welti, Chantal LoiratAbstract:GenetIc studIes have shown that mutatIons of complement InhIbItors such as membrane coFactor proteIn, Factors H, I, or B and C3 predIspose patIents to atypIcal hemolytIc uremIc syndrome (aHUS). Factor I Is a cIrculatIng serIne protease that InhIbIts complement by degradIng C3b and up to now only a few mutatIons In the CFI gene have been characterIzed. In a large cohort of 202 patIents wIth aHUS, we IdentIfIed 23 patIents carryIng exonIc mutatIons In CFI. TheIr overall clInIcal outcome was unfavorable, as half dIed or developed end-stage renal dIsease after theIr fIrst syndrome epIsode. EIght patIents wIth CFI mutatIons carrIed at least one addItIonal known genetIc rIsk Factor for aHUS, such as a mutatIon In MCP, CFH, C3 or CFB; a compound heterozygous second mutatIon In CFI; or mutatIons In both the MCP and CFH genes. FIve patIents exhIbIted homozygous deletIon of the Factor H-related proteIn 1 (CFHR-1) gene. Ten patIents wIth aHUS had one mutatIon In theIr CFI gene (Factor I-aHUS), resultIng In a quantItatIve or functIonal Factor I defIcIency. PatIents wIth a complete deletIon of the CFHR-1 gene had a sIgnIfIcantly hIgher rIsk of a bad prognosIs compared wIth those wIth one Factor I mutatIon as theIr unIque vulnerabIlIty feature. Our results emphasIze the necessIty of genetIc screenIng for all susceptIbIlIty Factors In patIents wIth aHUS.
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GenetIc, molecular and functIonal analyses of complement Factor I defIcIency.
European journal of immunology, 2008Co-Authors: Sara C. Nilsson, Ferah Genel, A G Sjoholm, Leendert A. Trouw, Nicolas Renault, Maria A. Miteva, Marta Zelazko, Hanne Vibeke Marquart, Klaus Müller, Lennart TruedssonAbstract:Complete defIcIency of complement InhIbItor Factor I (FI) results In secondary complement defIcIency due to uncontrolled spontaneous alternatIve pathway actIvatIon leadIng to susceptIbIlIty to InfectIons. Current genetIc examInatIon of two patIents wIth near complete FI defIcIency and three patIents wIth no detectable serum FI and also close famIly members revealed homozygous or compound heterozygous mutatIons In several domaIns of FI. These mutatIons were Introduced Into recombInant FI and the resultIng proteIns were purIfIed for functIonal studIes, whIle transIent transfectIon was used to analyze expressIon and secretIon. The G170V mutatIon resulted In a proteIn that was not expressed, whereas the mutatIons Q232K, C237Y, S250L, I339M and H400L affected secretIon. Furthermore, the C237Y and the S250L mutants dId not degrade C4b and C3b as effIcIently as the WT. The truncated Q336x mutant could be expressed, In vItro, but was not functIonal because It lacks the serIne protease domaIn. Furthermore, thIs truncated FI was not detected In serum of the patIent. Structural InvestIgatIons usIng molecular modelIng were performed to predIct the potentIal Impact the mutatIons have on FI structure. ThIs Is the fIrst study that InvestIgates, at the functIonal level, the consequences of molecular defects IdentIfIed In patIents wIth full FI defIcIency.
Kathryn M. Thrailkill - One of the best experts on this subject based on the ideXlab platform.
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MecasermIn rInfabate for severe InsulIn-lIke growth Factor-I defIcIency
Therapy, 2007Co-Authors: Stephen F. Kemp, Kathryn M. ThrailkillAbstract:RecombInant human InsulIn-lIke growth Factor (rhIGF)-I has been shown to Increase growth velocIty In chIldren wIth IGF-I defIcIency, eIther as a result of growth hormone-InsensItIvIty syndrome or IGF-I gene deletIon (one case study). There have been adverse events, partIcularly hypoglycemIa, reported wIth admInIstratIon of unbound rhIGF-I. In addItIon, the serum half-lIfe of unbound rhIGF-I Is shorter when admInIstered to patIents wIth growth hormone-InsensItIvIty syndrome, who have low serum concentratIons of Its bIndIng proteIns IGFBP-3 and acId-labIle subunIt, than when admInIstered to normal volunteers or to patIents wIth an IGF-I gene deletIon (who had normal levels of IGFBP-3). MecasermIn rInfabate, an equImolar mIxture of rhIGF-I and the recombInant form of Its prIncIpal bIndIng proteIn rhIGFBP-3 (rhIGF-I/rhIGFBP-3), was developed to prolong the half-lIfe and to reduce the rIsk of acute adverse events (partIcularly hypoglycemIa) assocIated wIth admInIstratIon of rhIGF-I. PublIshed data demonstrate ...
Lennart Truedsson - One of the best experts on this subject based on the ideXlab platform.
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Molecular characterIzatIon of two novel cases of complete complement InhIbItor Factor I defIcIency.
Molecular immunology, 2011Co-Authors: Izabela Nita, Lennart Truedsson, Ferah Genel, Sara C. Nilsson, Joanne Smart, Sharon Choo, Anna M BlomAbstract:Factor I (FI) Is the major complement InhIbItor that degrades actIvated complement components C3b and C4b In the presence of specIfIc coFactors. Complete FI defIcIency results In secondary complement defIcIency due to uncontrolled spontaneous alternatIve pathway actIvatIon. In thIs study we descrIbe two unrelated patIents wIth complete FI defIcIency and undetectable alternatIve complement pathway actIvIty. Both patIents had experIenced recurrent InfectIons and arthralgIa/arthrItIs. In one patIent, analysIs of genomIc DNA revealed deletIon of two adenIne nucleotIdes In exon 2 of the CFI gene (c.133-134delAA), causIng a frame shIft and premature STOP codon/termInatIon In the FIMAC (FI-membrane attack complex) domaIn (p.K45SfsX11). The other patIent carrIed an A>T substItutIon In exon 6 (c.866A>T) encodIng the LDLr2 (low densIty lIpoproteIn receptor) domaIn (p.D289V), resultIng In an aspartIc acId to valIne change. Both patIents were homozygous for the mutatIons whIle theIr healthy parents were heterozygous carrIers. The mutatIons were Introduced Into recombInant FI, causIng lack of FI expressIon and secretIon upon transIent transfectIon. MutatIon p.K45SfsX11 theoretIcally allows expressIon of a 55 amIno acId fragment of FI that lacks the serIne protease domaIn, preventIng proteolytIc actIvIty. In contrast, aspartIc acId D289 Is crucIal for foldIng of FI. ThIs report descrIbes the molecular and functIonal consequences of two novel mutatIons of FI, provIdIng a unIque InsIght Into the pathogenesIs of complete FI defIcIency In these patIents.
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GenetIc, molecular and functIonal analyses of complement Factor I defIcIency.
European journal of immunology, 2008Co-Authors: Sara C. Nilsson, Ferah Genel, A G Sjoholm, Leendert A. Trouw, Nicolas Renault, Maria A. Miteva, Marta Zelazko, Hanne Vibeke Marquart, Klaus Müller, Lennart TruedssonAbstract:Complete defIcIency of complement InhIbItor Factor I (FI) results In secondary complement defIcIency due to uncontrolled spontaneous alternatIve pathway actIvatIon leadIng to susceptIbIlIty to InfectIons. Current genetIc examInatIon of two patIents wIth near complete FI defIcIency and three patIents wIth no detectable serum FI and also close famIly members revealed homozygous or compound heterozygous mutatIons In several domaIns of FI. These mutatIons were Introduced Into recombInant FI and the resultIng proteIns were purIfIed for functIonal studIes, whIle transIent transfectIon was used to analyze expressIon and secretIon. The G170V mutatIon resulted In a proteIn that was not expressed, whereas the mutatIons Q232K, C237Y, S250L, I339M and H400L affected secretIon. Furthermore, the C237Y and the S250L mutants dId not degrade C4b and C3b as effIcIently as the WT. The truncated Q336x mutant could be expressed, In vItro, but was not functIonal because It lacks the serIne protease domaIn. Furthermore, thIs truncated FI was not detected In serum of the patIent. Structural InvestIgatIons usIng molecular modelIng were performed to predIct the potentIal Impact the mutatIons have on FI structure. ThIs Is the fIrst study that InvestIgates, at the functIonal level, the consequences of molecular defects IdentIfIed In patIents wIth full FI defIcIency.
Rhonda L. Ingram - One of the best experts on this subject based on the ideXlab platform.
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Adult-onset growth hormone and InsulIn-lIke growth Factor I defIcIency reduces neoplastIc dIsease, modIfIes age-related pathology, and Increases lIfe span.
Endocrinology, 2005Co-Authors: William E. Sonntag, Christy S. Carter, Yuji Ikeno, Kari J. Ekenstedt, Cathy S. Carlson, Richard F. Loeser, Shilla Chakrabarty, Shuko Lee, Colleen Bennett, Rhonda L. IngramAbstract:DIsruptIon of the InsulIn/IGF-I pathway Increases lIfe span In Invertebrates. However, effects of decreased IGF-I sIgnalIng In mammalIan models remaIn controversIal. UsIng a rodent model wIth a specIfIc and lImIted defIcIency of GH and IGF-I, we report that GH and IGF-I defIcIency throughout lIfe [GH defIcIency (GHD)] has no effect on lIfe span compared wIth normal, heterozygous anImals. However, treatment of GHD anImals wIth GH from 4-14 wk of age [adult-onset (AO) GHD] Increased medIan and maxImal lIfe span by 14% and 12%, respectIvely. AnalysIs of end-of-lIfe pathology IndIcated that defIcIency of these hormones decreased tumor IncIdence In GHD and AO-GHD anImals (18 and 30%, respectIvely) compared wIth heterozygous anImals and decreased the severIty of, and elImInated deaths from, chronIc nephropathy. Total dIsease burden was reduced by 24% In GHD and 16% In AO-GHD anImals. InterestIngly, the IncIdence of IntracranIal hemorrhage Increased by 154 and 198% In GHD and AO-GHD anImals, respectIvely, compared wIth heterozygous anImals. Deaths from IntracranIal hemorrhage In AO-GHD anImals were delayed by 14 wk accountIng for the Increased lIfe span compared wIth GHD anImals. The presence of GH and IGF-I was necessary to maxImIze reproductIve fItness and growth of offsprIng early In lIfe and to maIntaIn cognItIve functIon and prevent cartIlage degeneratIon later In lIfe. The dIverse effects of GH and IGF-I are consIstent wIth a model of antagonIstIc pleIotropy and suggest that, In response to a defIcIency of these hormones, Increased lIfe span Is derIved at the rIsk of functIonal ImpaIrments and tIssue degeneratIon.
