A Novel Splice Variant in the N-propeptide of COL5A1 Causes an EDS Phenotype with Severe Kyphoscoliosis and Eye Involvement 英文参考文献.docVIP

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A Novel Splice Variant in the N-propeptide of COL5A1 Causes an EDS Phenotype with Severe Kyphoscoliosis and Eye Involvement 英文参考文献.doc

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A Novel Splice Variant in the N-propeptide of COL5A1 Causes an EDS Phenotype with Severe Kyphoscoliosis and Eye Involvement 英文参考文献

ANovelSpliceVariantintheN-propeptideofCOL5A1 CausesanEDSPhenotypewithSevereKyphoscoliosis andEyeInvolvement SofieSymoens1*,FransiskaMalfait1,PhilipVlummens1,TrinhHermanns-Le?2,DelfienSyx1,AnneDe Paepe1 1CenterforMedicalGenetics,UniversityHospitalGhent,Ghent,Belgium,2DepartmentofDermatopathology,UniversityHospitalofSart-Tilman,Lie`ge, Belgium Abstract Background:TheEhlers-DanlosSyndrome(EDS)isaheritableconnectivetissuedisordercharacterizedbyhyperextensible skin,jointhypermobilityandsofttissuefragility.TheclassicsubtypeofEDSiscausedbymutationsinoneofthetypeV collagengenes(COL5A1andCOL5A2).MostmutationsaffectthetypeVcollagenhelicaldomainandleadtoadiminishedor structurallyabnormaltypeVcollagenprotein.Remarkably,onlytwomutationswerereportedtoaffecttheextended,highly conservedN-propeptidedomain,whichplaysanimportantroleintheregulationoftheheterotypiccollagenfibrildiameter. We identified a novel COL5A1 N-propeptide mutation, resulting in an unusual but severe classic EDS phenotype and a remarkablesplicingoutcome. Methodology/Principal Findings: We identifiedanovel COL5A1N-propeptideacceptor-splice sitemutation(IVS6-2A.G, NM_000093.3_c.925-2A.G)inapatientwithcutaneousfeaturesofEDS,severeprogressivescoliosisandeyeinvolvement. Twomutanttranscriptswereidentified,onewithanexon7skipandoneinwhichexon7andtheupstreamexon6are deleted.Bothtranscriptsareexpressedandsecretedintotheextracellularmatrix,wheretheycanparticipateinandperturb collagenfibrillogenesis,asillustratedbythepresenceofdermalcollagencauliflowers.Determinationoftheorderofintron removalandcomputationalanalysisshowedthatsimultaneousskippingofexons6and7isduetothecombinedeffectof delayedsplicingofintron7,alteredpre-mRNAsecondarystructure,lowsplicesitestrengthandpossiblydisturbedbinding ofsplicingfactors. Conclusions/Significance:WereportanovelCOL5A1N-propeptideacceptor-splicesitemutationinintron6,whichnotonly affectssplicingoftheadjacentexon7,butalsocausesasplicingerroroftheupstreamexon6.Ourfindingsaddfurther in