Fibrillin-1 Mutations Causing Weill-Marchesani Syndrome and Acromicric and Geleophysic Dysplasias Disrupt Heparan Sulfate Interactions 英文参考文献.docVIP

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Fibrillin-1 Mutations Causing Weill-Marchesani Syndrome and Acromicric and Geleophysic Dysplasias Disrupt Heparan Sulfate Interactions 英文参考文献.doc

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Fibrillin-1 Mutations Causing Weill-Marchesani Syndrome and Acromicric and Geleophysic Dysplasias Disrupt Heparan Sulfate Interactions 英文参考文献

Fibrillin-1MutationsCausingWeill-Marchesani SyndromeandAcromicricandGeleophysicDysplasias DisruptHeparanSulfateInteractions StuartA.Cain*,AmandaMcGovern,AndrewK.Baldwin,ClairBaldock,CayM.Kielty WellcomeTrustCentreforCell-MatrixResearch,FacultyofLifeSciences,UniversityofManchester,Manchester,UnitedKingdom Abstract The extracellular glycoprotein fibrillin-1 forms microfibrils that act as the template for elastic fibers. Most mutations in fibrillin-1causeMarfansyndromewithseverecardiovascularandocularsymptoms,andtallstature.Thisisincontrastto mutationswithinaheparin-bindingTBdomain(TB5),whichisdownstreamofthearg-gly-aspcelladhesiondomain,which cancauseWeill-Marchesanisyndrome(WMS)orAcromicric(AD)andGeleophysicDysplasias(GD).WMSischaracterizedby short limbs, joint stiffness and ocular defects, whilst fibrillin-1 AD and GD have severe short stature, joint defects and thickenedskin.WepreviouslyshowedthatTB5bindsheparin.Here,weshowthatthecorrespondingregionoffibrillin-2 bindsheparinverypoorly,highlightinganovelfunctionaldifferencebetweenthetwoisoforms.Thisfindingenabledusto mapheparin/heparansulfatebindingtotwositesonfibrillin-1TB5usingamutagenesisapproach.Oncethesesiteswere mapped,wewereabletoinvestigatewhetherdisease-causingmutationsinthisdomaindisruptbindingtoHS.Weshow that a WMS deletion mutant, and five AD and GD point mutants all have disrupted heparin binding to TB5. These data provideinsightsintothebiologyoffibrillinsandthepathologiesofWMS,ADandGD. Citation: Cain SA, McGovern A, Baldwin AK, Baldock C, Kielty CM (2012) Fibrillin-1 Mutations Causing Weill-Marchesani Syndrome and Acromicric and GeleophysicDysplasiasDisruptHeparanSulfateInteractions.PLoSONE7(11):e48634.doi:10.1371/journal.pone.0048634 Editor:XinZhang,IndianaUniversitySchoolofMedicine,UnitedStatesofAmerica ReceivedAugust3,2012;AcceptedSeptember28,2012;PublishedNovember2,2012 Copyright:?2012Cainetal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsunr