Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of

Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of homozygosity region onchromosome 3q28–q29

JournaloftheNeurologicalSciences359(2015)351–355

ContentslistsavailableatScienceDirect

JournaloftheNeurologicalSciences

journalhomepage:/locate/jns

Microarrayanalysisunmaskedtwosiblingswithpurehereditaryspasticparaplegiasharedarunofhomozygosityregiononchromosome3q28–q29

WenqianYua,1,XiangdongYoub,1,DongWanga,KaiDonga,JingSuc,ChuanfenLic,JinxiuLiua,QianqianZhanga,FengYoua,XiangrongWanga,JingHuanga,BinQiaoa, ,2,WenyuanDuana, ,2

abc

InstituteofCardiovascularDisease,GeneralHospitalofJinanMilitaryRegion,8LashanRoad,Jinan250022,China

DivisionofQualityManagement,ShandongCenterforDiseaseControlandPrevention,16992JingshiRoad,Jinan250014,ChinaDepartmentofNeurology,GeneralHospitalofJinanMilitaryRegion,25ShifanRoad,Jinan250031,China

articleinfoabstract

Hereditaryspasticparaplegia(HSP)isaclinicalandgeneticheterogeneitygroupofneurodegenerativedisorderswhichischaracterizedbyprogressiveweaknessandspasticityofthelowerlimbs.Morethan70genetictypesofHSPhavebeendescribedsofar.HerewedescribeaChinesenon-consanguineousfamilywithtwoaffectedsiblingsmanifestingearly-onsetautosomalrecessiveHSPinpureforms.Toidentifygenotypeandcharacterizephenotype,CytoScanHDarrayanalysiswasperformedonthetwosiblings.Arunofhomozygosity(ROH)sharedbythetwopatientswasdetectedonchromosome3q28–q29.TheROHregion,about7.7Mbonthechromosome3:190172058-197851260partiallyoverlappedwiththeROHregionofSPG14previouslyreported.Subsequently,microsatelliteanalysiscon rmedthisROHandwhole-exomesequencingwascarriedoutwhilenocausativemu-tationswerefoundintheexonsofknownHSPgenesand68candidategenesinthatregion.Inconclusion,ourdatasuggesttheROHinthisregionmayplayapivotalroleinSPG14pathogenesis.Thisisthe rstclinicaldescriptionofapureformspasticparaplegiainanon-consanguineousfamilyassociatedwiththeSPG14locus.

©2015ElsevierB.V.Allrightsreserved.

Articlehistory:

Received12January2015

Receivedinrevisedform21October2015Accepted27October2015

Availableonline4November2015Keywords:

HereditaryspasticparaplegiaMicroarray3q28–q29

RunofhomozygositySPG14

Autosomalrecessive

Neurodegenerativedisorder

1.Introduction

Hereditaryspasticparaplegia(HSP)isoneofthemostclinicallyandgeneticallyheterogeneousgroupsofinheritedneurodegenerativedisordersmainlycharacterizedbyslowlyprogressivelower-limbspas-ticitywhichworsensovertime.Theneuropathologic ndingistheresultofthelongmotoraxonsofthecorticospinal-tractdegeneration[1–3].Themodesofinheritanceincludeautosomaldominant(AD-HSP),autosomalrecessive(AR-HSP),X-linkedormitochondrialtrait[4,5].Clinically,HSPsareclassi edaspureandcomplicatedforms.ThecomplicatedHSPsarecombinedwithfurtherneurologicalandsystemicabnormalities,whereasthepureformsessentiallyexhibitedlowerlimbweaknessandspasticity.Todate,morethan70differentlocihavebeenmappedand55spasticparaplegiagenes(SPGs)wereidenti ed.ThecorrespondingproteinsofSPGsplaykeyrolesintheregulationofintracellularmembranetraf cking,endoplasmicreticulummembrane

shaping,DNArepair,autophagy,mitochondrialfunction,lipidmetabo-lismandmyelinformation[6–8].

SPG14isanautosomalrecessiveformofHSPwhichhasbeenmappedtoacandidatediseaselocusonchromosome3q27–q28be-tweenmarkersD3S1580(chr3:188542793–188543136)andD3S3669(chr3:192501965–192502314)[9].Bynowonlyasingleconsanguine-ousItalianfamilywiththreeaffectedsubjectspresentingacomplexphenotypeincludingmildmentalretardationandmilddistalmotorneuropathyhasbeendescribed.

Herein,wereportedtwosiblingsborninanon-consanguineousChinesefamilywithspasticparaplegia.TheclinicalmanifestationsofourpatientspresentapureformofHSP.SNPmicroarraycon rmedanROHonchromosome3q28–q29ofthetwoaffectedsiblingsthatpartiallycoincidedwiththeregionofSPG14inthepreviousreport.2.Patientsandmethods2.1.Patients

Correspondingauthors.

E-mailaddresses:cijnmd@(B.Qiao),dwy2115@(W.Duan).1

The rsttwoauthorscontributedequallytothiswork.2

Thetwocorrespondingauthorscontributedequallytothis

work.

Thepresentstudyinvolvedtwosiblingsfromafamilywithpurespasticparaplegia.ThefamilypedigreeisshowninFig.1.Theirparentsarenon-consanguineousmarriage,andtheirfatherdiedofcirrhosis

/10.1016/j.jns.2015.10.057

0022-510X/©2015ElsevierB.V.Allrights

reserved.

Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of homozygosity region onchromosome 3q28–q29

352W.Yuetal./JournaloftheNeurologicalSciences359(2015)351–355

Fig.1.PedigreeoftheAR-HSPfamily.Thehaplotypesarecomposedof fteenmicrosatellitemarkersfromchromosome3q28–3q29.Longgreenbarsindicatethehomozygosityregionthatissharedbythetwopatients(betweenD3S1288toD3S3707).

7yearsago.Twoaffected(III-1andIII-2)andsixunaffectedmembers(II-2–4andII-6–8)wereexaminedbytwoexperiencedneurologists(Dr.Q-LSongandDr.JSu).Additionally,theaffectedindividualstooktheexaminationofmagneticresonanceimaging(MRI)andelectroen-cephalogram(EEG)analysis.

2.3.Exomesequencing

Paired-endsequencingwasperformedonIlluminaGAIIx/HiSeq2000instruments(Illumina,SanDiego,CA,USA)availableatShanghaiBiotechnologyCo.,Ltd.ExoncapturewasconductedusingAgilentSureSelectTechnology(Agilent,SantaClara,CA,USA).Forsequencealignment,variantcallingandannotation,thesequencesweremappedtotheirlocationwiththehumangenomereferencesequence(hg19build)usingaBurrows-WheelerAligner.Localrealignmentofthepotentialinsertion/deletionsiteswascarriedoutwithaGenomeanalysistool(GATK).SNPandindelvariantswereperformedagainstreferencedbSNP138.Allvariantswereannotatedwithreferencetocon-sensuscodingsequences(CCDS)(NCBIrelease20090902)andRefSeq(UCSCdumped20101004).ThenovelvariantswerecheckedwiththeIntegrativeGenomicsViewer(IGV),andthenfurtherinvestigatedinthefamilyandnormalChinesepopulation.3.Results3.1.Clinicaldata

ThepatientsaretwosiblingsfromaHanChinesefamily.Theeldersister(III-1)iscurrently18yearsold.Shewasbornattermwithanuneventfuldelivery.Sheexperiencedprogressiveweaknessofthelegsandtumbledseveraltimessincenine.Overthenextfewyears,gaitim-pairmentprogressedcontinuously;footdropandfootinversionwerepresentinherrightside.Atthetimeofadmissiontoourhospital,shewasbedriddenwithverylittlemobilityinherlegs.Theyoungerbrother(III-2)iscurrentlytenyearsold.Hewasnoticedslowlyprogressiveweaknessoflegsandgaitdisturbanceat7yearsold.Withthe

passage

2.2.Homozygositymapping

TotalgenomicDNAofthetwosiblingsandtheirmotherwereisolat-edandpuri edfromperipheralbloodusingtheQIAampDNAbloodminikit(Qiagen,Valencia,CA,USA).Then,theDNAsampleswereana-lyzedbyCytoScanHDarraysaccordingtothemanufacturer’sprotocol(Affymetrix,SantaClara,CA,USA).Brie y,250ngDNAwasdigestedwithNspIandligatedtoadaptersforsubsequentPCRampli cation.Theampli cationproductswerepuri edusingpuri cationbeads,fragmented,labeled,andhybridizedfor16–18hintheGeneChipHybridizationOven,ThearrayswerethenwashedwithaGeneChipFluidicsStation450,andscannedwithaGeneChipScanner30007G(Affymetrix).CopynumberandROHanalysiswereperformedusingtheAffymetrixChromosomeAnalysisSuitesoftware.

Fifteenmicrosatellitemarkerson3q28–q29includedD3S1580,D3S3530,D3S1294,D3S1288,D3S2747,D3S3043,D3S1601,D3S3663,D3S3669,D3S1523,D3S2305,D3S1305,D3S1272,D3S3707andD3S3550,nineofwhichwereconsistentwithG.Vazzaetal.[9]previ-ouslyreported.GenomicDNAoftheprobands,theirmotheranduncleswereextractedandusedforampli cations.FragmentswereanalyzedusinganABIPrism3730GeneticAnalyzer(AppliedBiosystems,ForsterCity,CA,USA)withthedenaturingPOP7polymer.ElectropherogramswereanalyzedusingGeneMappersoftware.

Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of homozygosity region onchromosome 3q28–q29

W.Yuetal./JournaloftheNeurologicalSciences359(2015)351–355353

oftime,heshowedslurredspeechandmildfootdrop.Hecanwalkwiththehelpofwalkingaidswhenarrivedatourhospital.Neurologicexam-inationofthetwopatientsrevealedweaknessandspasticityinthelowerlimbswithpositivepyramidaltractsigns(hypertonicityofthelowerlimbs,markedbilateralankleclonusandbilateralBabinskisigns),pescavusandplantarhypermyotonia.Noneofthemdisplayedabnormalitiesonelectroencephalography(EEG).Theirbrainswerealsonormalbasedonmagnetic-resonanceimaging(MRI).Atthetimeofrecentvisit,theeldersisterwascon nedtobedwithmalnutritionandamyotrophy,whichmightbepartiallyascribedtodisuseatrophy.Nystagmuswasobservedinbothpatients.ThedetailedinformationissummarizedinTable1.Bothofthemwereclassi edaspureHSPbytwoexperiencedneurologists(Dr.Q-LSongandDr.JSu).ExceptforIII-1andIII-2,otherindividualsfromthisfamilyarenormalinclinicalmanifestationsandauxiliaryexaminations.

3.3.Mutationanalysis

Whole-exomesequencingwasperformedontheIII-1,III-2andII-6.Theresultscovered93%ofthetargetregionwiththemedianreaddepth(102×,100×and81×),26,033SNPsand258indelswereidenti ed.SinceHSPwasassumedtobeaveryrareconditionandnoclinicalsig-ni cantmutationinknownHSPgeneswasdetected,weexcludedheterozygouschanges,changesnotsharedbytheaffectedsiblingsandhomozygouschangesconsistentwiththeirmother.Tenhomozygousvariationswithafrequencyofb1%indbSNP138wereidenti ed,twoofwhichwerein5′UTRregionsandonewasintheintronicregion.Thefrequencyofthesethreevariantsrangedfrom0.1to0.4%referencedinthedbSNP138(rs185421189,rs147536472andrs191327348).NoneofthemwaslikelypathogenicsincetheydidnotaffectsplicesitesthroughpredictionbytheHumanSplicingFinder(HSF).Thesevenre-mainingvariantswerelocatedinexoncodingsequences,threeofthemweremissensevariantsinC3orf43,CRLF1andKIR3DL1genespreviouslyreportedinthedbSNP138,HapMap,and1,000GenomesDatabase(rs118152136,rs117193413andrs150084719respectively),theywerepredictedasbenignbySIFTandPolyphen2predictionpro-grams.Theremainingweresynonymousmutations,twoofwhichhadfrequency0.5%indbSNP138(rs35480846,rs139525246),andwerepredictedtobenon-pathologicbyHSF.Theothertwonovelsynony-mousvariant,oneofwhichlocatedatthe rstexonoftheMUC4gene(c.G10605C),theotherwasavariantintheFBXO45genec.33CNT.However,theywerebothpredictednottoaffectadjacentsplicesitesoractivatecrypticsplicesites.

Furthermore,Sangersequencingwasperformedontheexonsandpromoterregionsofcandidateeightgenes(IL1RAP,GEMC1,SNAR-I,OSTN,UTS2D,CCDC50,PYDC2andFGF12).27variantswereidenti ed,ninelocatedinexonoruntranslatedregions(UTR)regions.TheSangersequencingresultsoftheninevariantswereconsistentwiththoseofexomesequencing(SupplementTable2).Asthephenotypeofourpa-tientsappearedtobeanautosomalrecessivemodel,wefocusedonho-mozygousmutationsintheaffectedindividualsthatwereheterozygousintheirmother.Fourhomozygousvariationswithafrequencyofb1%indbSNP138wereidenti ed(markedwithboldfont).However,noneof

3.2.Theresultsofhomozygositymapping

Thecytogeneticsrevealednormalkaryotypes(46,XXand46,XY)inthetwosiblingswithnoabnormalitydetected.Microarrayanalysisofthetwosiblingsandtheirmotherdidn'tidentifyanyclinicalsigni canceregionsofcopynumbervariation.Assmallerstretchesofhomozygosity(b3Mb)spreadthroughoutthegenomearecommoneveninoutbredpopulations[10],wesetasizethreshold(N3Mb).Thesegmentsbelow3Mbwerenotconsideredtobesigni cant.AnROHonthechro-mosome3q28–q29(Fig.2)wasdetectedinthetwosiblings,whichwasabout7.7Mbandcoveredthebasepairpositionsfrom190172058to197851260(hg19)including68genes.Moreover,thisregionpartiallyoverlappedwiththeSPG14locusandtheoverlappingregionincluded8genes(IL1RAP,GEMC1,SNAR-I,OSTN,UTS2D,CCDC50,PYDC2andFGF12)(SupplementTable1).

Tocon rmthehomozygositysharedbythetwosiblings,wegenotypedpolymorphismsusing15single-nucleotidemicrosatellitemarkersinfamilymembers.Theresultscon rmedtheROHregionofthetwosiblingsonthetelomereofchromosome3betweenmarkersD3S1288andD3S3707(Fig.1).

Table1

Clinicalfeaturesoffamilieswith3q28–q29ROH

PresentfamilyIII-1

ROHregionEthnicitySex

Ageatexamination,yAgeatonset,ySymptomatonsetUpperlimbsSpasticityWeaknessHyperre exia

LowerlimbsSpasticityAnkleclonusAmyotrophyWeaknessHyperre exiaDystoniaBabinskisignPescavus

ExtensorplantarresponsesWalkingabilityCognitivedeclineNystagmusEEGMRI

a

G.Vazzaetal

III-2

Chinese-HanMale107

Weaknessoflowerlimb

II-2

II-6

II-8ItalianFemale52

Spasticgait

Chr3:190172058–197851260Chinese-HanFemale189

Weaknessoflowerlimb;spasticgaitChr3:188542793–192502314ItalianItalianMaleFemale6254

Average30

SpasticgaitSpasticgaitNRaNRNR

––––––NRNRNRNRNRNR

+++++++++

Walker–

+(mild)NormalNormal++–++++++

Walker–

+(mild)NormalNormal+NRNR+++NR++

Unaided+NR

NormalNormal+NRNR+++NR++

Unaided+NR

NormalNR+NRNR+++NR++

Unaided+NR

NormalNR

NRindicates“NotReported”.

Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of homozygosity region onchromosome 3q28–q29

354W.Yuetal./JournaloftheNeurologicalSciences359(2015)351–355

Fig.2.(A)Thesiblingswithacompletesimilarregionofrunofhomozygosity(ROH)onchromosome3whichisabsentintheirmother.(B)SNPdatadisplayedinChASshowingtheROHfrom3q28.3to3qter.

thevariantswerelikelypathogenicsincetheywerenotinclinedtoaf-fectsplicesitesaccordingtothedataofHSF.

4.Discussion

Inthisresearch,wedescribetwopatientsfromanon-consanguineousfamilywithpurespasticparaplegia.Afterexcludingthecontributionofcopynumbervariationincludingdeletionsandduplications,anROHonchromosome3q28–q29wasidenti ed.Theregionwasabout7.7Mbonthechromosome3:190172058–197851260including68geneswhichpartiallycoincidedwithSPG14region.Theoverlappingregionincluded8genes(IL1RAP,GEMC1,SNAR-I,OSTN,UTS2D,CCDC50,PYDC2andFGF12).Subsequently,theROHregionwascon rmedbymicrosatelliteanalysis.

Longcontiguousstretchesofhomozygositycanbeassociatedwithconsanguinityoruniparentaldisomy,bothofwhichincreasetheriskofautosomalrecessivediseases[11].TheconservativeclinicalsetathresholdsforROHbetween3and10Mb,whenasecondchromosomehadaROHN10Mb,indicatingidentitybydescentandconsideringex-clusionofpatientsfromuniparentaldisomy[12,13].OurpatientIII-1hasa7.7MbROHonthelongarmofchromosome3and11.4MbROHonthechromosome6p(SupplementFig.1),whichwaslikelytoindi-catehomozygositybyvirtueofparentaldescentfromacommonances-tor[14–16].

AR-HSPcausedbySPG14ischaracterizedbyprogressivespasticity,hyperre exia,andmildlower-limbhypertonicitywiththe30yearsaverageageofonset[9].Allaffectedmembersshowedneuropsycho-logicalimpairmentandbilateralpescavusandnonedisplayedabnor-malitiesonelectroencephalography[9].Thetwosiblingsinourstudyexperiencedonsetat9and7yearsold,respectively.Themainclinicalmanifestationsofthetwopatientswerespasticparaplegiaofthelowerlimbs,partiallyaccompaniedwithpescavus,amyotrophy,andmildnystagmus.AllofthesemanifestationsinourpatientsindicatedapureformofHSP.AlthoughitisnotpossibletoinferthatthesamegeneisresponsibleforSPG14andthediseaseinourfamily.Phenotypi-calvariabilitycausedbyalleleheterogeneityhasbeenobservedinmanydisordersincludingHSP[17–19].

TheexomesequencingresultsrevealedthattherewasnopathogenicmutationintheROHregionandotherchromosomes.Sangersequencingcon rmedtheexomesequencingresultoftheeightgenes(IL1RAP,GEMC1,SNAR-I,OSTN,UTS2D,CCDC50,PYDC2andFGF12)inROH,andnocausativemutationwasfoundinpromoterregionsofthosegenes.Sincethemicroarrayanalysisdetecteda7.7MbROHregiononchromo-some3q28–q29andsubsequentlycon rmedbymicrosatellitemarkers.WespeculatedthattheintervalofSPG14mightbelongerthanpreviousthoughtfromchromosome3:190172058tochromosome3:197851260.Therewere68genesintheROHregion,someofwhichseemtoberelat-edwithspasticparaplegia.PreviousstudiesshowedthatFGF12knockoutmicedisplaymuscleweaknessandFGF12-/-/FGF14-/-mice

represented

Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of homozygosity region onchromosome 3q28–q29

W.Yuetal./JournaloftheNeurologicalSciences359(2015)351–355355

severeataxiabehavior[20,21],andFGF12mightberelatedtoHSPinhuman;theubiquitinligaseF-boxprotein45(FBXO45)iscriticalforsyn-aptogenesis,synaptictransmissionandneuronalmigrationindevelop-ingcentralandperipheralneurons[22].RecentresearchsuggestedthatFBXO45mightbeacandidategeneforschizophreniaandcerebralpalsy[23,24].Therefore,furtheranalysisofnon-codingregions,intronicandmRNAexpressionofthegenesinthecriticalROHregionneedtobeconductedtoidentifythegenesresponsibleforSPG14.

Inconclusion,weidenti edthe rstpureformofHSPinaChinesenon-consanguineousfamilywitha7.7MbROHonchromosome3q28–q29whichpartiallyoverlappedthelocusofSPG14.TheseresultssuggestedthatthesharedROHregiondetectedinourpatientshelpedtocon rmthecandidateregionon3qterassociatedwithSPG14.

Supplementarydatatothisarticlecanbefoundonlineat/10.1016/j.jns.2015.10.057.Con ictofinterest

Theauthorsdeclarenocon ictsofinterest.Acknowledgments

Theauthorsaregratefultoallthepeoplewhoprovidedhelpforthisstudy.ThisworkwassupportedbythegrantsfromtheNationalBasicResearchProgramofChina,(2013CB945402,2013CB945403).References

[1]J.K.Fink,Advancesinthehereditaryspasticparaplegias,Exp.Neurol.184(Suppl.1)

(2003)S106–S110.

[2]A.E.Harding,Classi cationofthehereditaryataxiasandparaplegias,Lancet1

(8334)(1983)1151–1155.

[3]C.M.Tallaksen,A.Durr,A.Brice,Recentadvancesinhereditaryspasticparaplegia,

Curr.Opin.Neurol.14(4)(2001)457–463.

[4]J.Finsterer,etal.,Hereditaryspasticparaplegiaswithautosomaldominant,recessive,

X-linked,ormaternaltraitofinheritance,J.Neurol.Sci.318(1-2)(2012)1–18.[5]H.Shimazaki,etal.,AhomozygousmutationofC12orf65causesspasticparaplegia

withopticatrophyandneuropathy(SPG55),J.Med.Genet.49(12)(2012)777–784.

[6]C.Blackstone,Cellularpathwaysofhereditaryspasticparaplegia,Annu.Rev.

Neurosci.35(2012)25–47.

[7]J.K.Fink,Hereditaryspasticparaplegia:clinico-pathologicfeaturesandemerging

molecularmechanisms,ActaNeuropathol.126(3)(2013)307–328.

[8]T.LoGiudice,etal.,Hereditaryspasticparaplegia:clinical-geneticcharacteristics

andevolvingmolecularmechanisms,Exp.Neurol.261(2014)518–539.

[9]G.Vazza,etal.,Anewlocusforautosomalrecessivespasticparaplegiaassociated

withmentalretardationanddistalmotorneuropathy,SPG14,mapstochromosome3q27–q28,Am.J.Hum.Genet.67(2)(2000)504–509.

[10]C.W.Rehder,etal.,AmericanCollegeofMedicalGeneticsandGenomics:standards

andguidelinesfordocumentingsuspectedconsanguinityasanincidental ndingofgenomictesting,Genet.Med.15(2)(2013)150–152.

[11]M.Manning,L.Hudgins,Array-basedtechnologyandrecommendationsforutiliza-tioninmedicalgeneticspracticefordetectionofchromosomalabnormalities,Genet.Med.12(11)(2010)742–745.

[12]P.Papenhausen,etal.,UPDdetectionusinghomozygositypro lingwithaSNP

genotypingmicroarray,Am.J.Med.Genet.A155A(4)(2011)757–768.

[13]K.L.Sund,etal.,Regionsofhomozygosityidenti edbySNPmicroarrayanalysisaid

inthediagnosisofautosomalrecessivediseaseandincidentallydetectparentalbloodrelationships,Genet.Med.15(1)(2013)70–78.

[14]L.H.Li,etal.,Longcontiguousstretchesofhomozygosityinthehumangenome,

Hum.Mutat.27(11)(2006)1115–1121.

[15]J.H.Schuurs-Hoeijmakers,etal.,Homozygositymappinginoutbredfamilieswith

mentalretardation,Eur.J.Hum.Genet.19(5)(2011)597–601.

[16]M.A.Nalls,etal.,Extendedtractsofhomozygosityidentifynovelcandidate

genesassociatedwithlate-onsetAlzheimer'sdisease,Neurogenetics10(3)(2009)183–190.

[17]P.Ribai,etal.,AnewphenotypelinkedtoSPG27andre nementofthecritical

regiononchromosome,J.Neurol.253(6)(2006)714–719.

[18]M.Muglia,etal.,AnovelKIF5AmutationinanItalianfamilymarkedbyspastic

paraparesisandcongenitaldeafness,J.Neurol.Sci.343(1-2)(2014)218–220.

[19]A.Aulitzky,etal.,Acomplexformofhereditaryspasticparaplegiainthreesiblings

duetosomaticmosaicismforanovelSPASTmutationinthemother,J.Neurol.Sci.347(1-2)(2014)352–355.

[20]M.Goldfarb,Fibroblastgrowthfactorhomologousfactors:evolution,structure,and

function,CytokineGrowthFactorRev.16(2)(2005)215–220.

[21]E.K.Wittmack,etal.,Fibroblastgrowthfactorhomologousfactor2B:association

withNav1.6andselectivecolocalizationatnodesofRanvierofdorsalrootaxons,J.Neurosci.24(30)(2004)6765–6775.

[22]T.Saiga,etal.,Fbxo45formsanovelubiquitinligasecomplexandisrequiredfor

neuronaldevelopment,Mol.Cell.Biol.29(13)(2009)3529–3543.

[23]A.Fernandez-Jaen,etal.,Cerebralpalsy,epilepsy,andsevereintellectualdisabilityin

apatientwith3q29microduplicationsyndrome,Am.J.Med.Genet.A164A(8)(2014)2043–2047.

[24]C.Wang,etal.,NovelrarevariantsinF-boxprotein45(FBXO45)inschizophrenia,

Schizophr.Res.157(1-3)(2014)149–156.

本文来源：https://www.bwwdw.com/article/5u44.html