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WILEY_

    BLACKWELLUsP26hnplotypesnndmntehqrtilityinthemeninT”twnn,China

    ;DOI:10.1111,j.17457262.2008.0H0439.x

    

    ;0r’

    ;Associati0nofUSP26hap1otypesinmeninTaiwan,China

    ;withseverespermatogenicdefectW1tnSeVereSpermatogenlCCLeteCt ;IWenLee,LongChingKuan,ChienHungLHsien-AnPan,ChaoChinHsu4,Yun

    gChiehTsai,Pa0LinKuo,

    ;YenNiTeng.

    ;D,nD6fPfc&IyncDZDI;affo,zfC,2ggfV,cDffgD

    cfnP,zfn,z7D,zw,(

    ;DprPf00ffrc,zdGvcrJf0DGP,zP,ZDpf,Zf,z7DD,fw,z,(:

    ;3InstitHteofBas{cSciences.NCi

    ;Abstract

    ;Aim:Tl0cOmp1etecomDrehensivehaplotVpeanalVsisOfSP26f0rbothfertileandinferti1emen.MethOds:Two

    ;hundredinfenilemenwithsevereo?gospermiaornonobstructiveazoosperrniaweresub

    jectedtosequenceana1ysis

    ;f0rtheentirecOdingsequencesOftheP26gene.TwOhundredmenwithprOvenfertiljtyweregenOtypedby

    ;primerextensionmethods.Al1ele/gen0tvpefrequencies,linkagedisequilibrium(LD)characteristicsandhaplotypesof

    ;fertilemenwerecomparedwithinfertilemen.Results:Theallelefrequencies0ffivesinglenuc1eOtidepOlymOr

    ;phisms(37037linsACA,494T>C,576G>A,ss6202791C>T,l737G>A)weresignificant1yhigherininfenilepatients

    ;thancontrolsubects.Themaiorhap1otvpesininfertilemenwere11ACCGA(28%ofthepopulati0n),TGCCGA

    ;f15%),TACCAA(8%),TGCCAA(6%),TATCAA(5%)andCATCAA(5%).Thema{orhapl0typesforthecontrol

    ;sub{ectswereTACCGA(58%ofthepopulation),CACCGA(7%),CATCGA(6%)andTGCCGA(5%).Haplotvpes

    ;TGCCGA,TATCAA,CATCAA,CATCGC,TACCAAandTGCCAAwereOver_transmittedinpatientswichspematO

    ;genicdefect,whereashaplOtVpesTACCGA,CACCGA,andCATCGAwereunder.transmittedinthesepatients.

    ;ConcIusiOn:SomeP26allelesandhaplotVpesareassociatedwithspematogenicdefectintheHannationa1itVin

;raiwan,China.nA,f2DD8?DJD8969D)

    ;Keyw0rds:singlenucleotidepolymorphism;26gene;spem1at0genicdefect;linkagedise

    qui1ibrium

    ;Correspondenceto:Prof.YenNireng,DeDartmentofBiote

    ;chnol0gv.ChiaN.dnUniversicvofPhar|ndcvandScience,60ErhJen

    ;Road,Sec.1.Pa0An,JenTeHsiang,Tainan717,Tlaiwan,China. ;I1el:+886626649l1ext.2549Fax:+88662662135

    ;Emai1:tengyennI1@yahO0.com.tw

    ;Received20080220AcceDted20080703

    ;896?

    ;1Intr0ducti0n

    ;Inflerti1ityaflfectsOnein10cOupleswOrldwide.In ;rOughlyhalf0fthesecOuples,themalefactOris ;imp1icated.Althoutherearemanyfactorsthatcon

    ;tributet0maleinferti1ity,thecausecannotbeidentified ;florthemajorityofinfenilemen1].Inrecentyears,there

    ?20O8,AsianJourna1ofAndrology.SIMMandSJTU.AllrightsreserVed

    6):8969O4 ;AsianJAndrot2o08:lo

    ;hasbeenanintensivesearchf_0rgeneticcauses0fmale ;inferti1ity.ScreeningwithmarkersOnthelOngarmOf ;mehumanYchr0mOsOmehasdetectedYlamicrOdeletiOns ;in5%15%0fmaleswithspermatogenicdefect.Itis ;believedthatmanygenesIocatedonthelong(q)annof ;theYchr0mOsOmearerequiredf0rspem1atOgenesis.This ;regiOn,bandinginql1.23OftheYchr0mOsOme,includes eazoospermiafact0r(A2:F)locus,whichcontajnsagene ;orgenesthatarerequiredf0rnorn1alspematogenesis2,

    ;3.0thergeneticfactorsthathavebeenreponedtobe ;invO1vedinspermatogenicdeflectincludemutatiOnsat ;themitOchOndrialDNApOlymeraselOcus,apOlVmOr

    ;phismOfthecytOchrOmeP4501A1gene,mutatiOnsOf ;thefolliclestimuIatinghonnonereceptorgene(,,the ;deletedinazoospern1ialikegene(),thesvnaptone

    ;malcomplexprotein3gene(l,CP),humanBD,

    ;caseinkinase2alphagenes,dystrophiamVOtonicaprO

    ;teinkinasegene(DP,DNApo1vmerasegamma

    ;(PDLG),methv1enetetrahvdmfl0latereductaserFR)

    ;,dndf0llicle.scimulatinghorn1onereceptor()4l61.

    26appearst0beanattractivecandidatef0ra ;sterilegenecOnsideringitsuniqueexpressiOnpattern. ;E,26cOn1prisesasingleexOnandisIOcatedOnXq26.2. ;ItsmessengerRNA(mRNA)sequenceis2794bplong ;anditsproteinconsistsof913aminoacidsfGenbank: ;NM031907.1).Itsmousehomologwasf0undtobe

;onlyexpressedinspermatogonia[17].P26belongs

    ;toalaefamilyofdeubiquitinacingenzymes(DUB)[18.

    ;Deubiquitinationofmacr0moleculesbyDUB,including ;ubiquitinprOteases,canrescuemacrOmOleculesfrOm

    specifjc,Ntermina1. ;degradatiOnthrOughsubstrate

    ;dependent,enzymaticreaction[19,201.Previousstudies ;haveaddressedthein1pOrtanceOftheubiquitinpath

    ;wayduringmammalianflenilizatiOn,includingacmsOmaI ;functionandspematozoazonapeUucida(ZP)penetfa

    ;tion[2l,22].Duringspematogenesis,deubiquitination ;enzVmeshavebeenshOwntobeinvOlvedintheregula

    ;tionofproteinturnover(e.g.,replacementofhistones ;byprOtamine,germcellapOptOsis,mitOticpr0liferatiOn ;anddiff_erentiationofspennatogonialstemcells)23

    ;28].Severa1papershavebeenpub1ishedontheroleof ;26inmaleinfertity.Stouflfsf,.291analvzed

    ;patientswimvariOushistOlOgicalpattemsOfspeatO

    ;genicdeflect(Sertolicel1.onlysyndromeandmaturation ;arrest)fOrthepresenceofmutationsinP26_Thev

    ;foundsomeSertolice11.onlysyndrome(SCOS)patients ;hadtIlegenotype0f370371insACA(rs3840975),49411>C ;andl423C>T(rs41299088)[29.AstudybvPaduch

    ;Te|:+86-21.5492-2824;Fax:+86-21_5492?2825;shanghai,China

    ;alsOprOvidedevidencelinking,5P26mutatiOntOmale

    ;infenility[30].Althoughthesetwostudiessuggestedthat ;aspecincgeneticcluster(37O37linsACA,494T>Cand

    ;1423C>T)mightbeassociatedwithtesticular ;dysf_unctiOn,tw0OtherstudiesshOwedthatthisgenetic ;clusterwasnotrestrictedtOmenwithtesticulardvs

    ;function[31,32.Inarecentpublicationon26,the

    ;authOrsidentifiedseveralnOvelmutatiOnsinthe(P26 ;genetnat?ugntcausespennatOgenes1slmpa1ment1na ;smallgroupofinfertilemen(,2=41)f33].However, ;meta—analysisofprevi0uscase.contro1studies”ntota1.

    ;544patientsand1705contro1s)revealednosignificant ;assOciai0n0fthe370371insACA.494T>CaJ1dl423C>T ;genocypewithmaleinfertility[14,2932].Furtherstudies

    ;basedOnalaregrOupOfpatientswithdiversifledethnic ;backgrOundswillbevaluabletObrjngmOreinsightintO ;therO1eOf)26inmaleinfertilitv.

    ;1nthepresentstudy,wesetOuttOanalVzegenetic ;variantsandhaplotypesOfLP26f0rbOthfertileand ;in1.eItilemenbysequencea1a1Vsisf0rtheentirecOdingre.

    ;giOnOfP26.W_efl0undsOme.5P26geneticvants ;andhaplOtypeswereOverttransmittedandsomewere

    ;undertransmittedinpatientswithseverespematOgenic ;defectintheHannatjOnalitvin11aiwan.China.W_ealsO ;identifjedsomenOve1geneticvariants0rmutationsin ;patients.Ourresu1tsupportsimpOnantr0lesOfP26 ;inhumanspermatOgenesis.

    ;2MaterialsandmethOds

    ;2.jSHbjects

    ;ThesmdywasapprOvedbymeInstitutiOna1Review ;BOardOfNaciOna1ChengKungUniversityMedica1Centre ;(raiwaJ1,China).Flr0mJanuarV2001toDecember2005. ;200infenilemenpresentingwimsevereoligOzOOspe?nia

    ;(spermatozoacount<5×l06/mL)ornonobstructive

    ;azoospemiaand200menwithpmvenfertilitv(control ;group)wereenrolled.AUofthecontrolsubiectshadfa

    ;theredatleasttwOchildrenwithin5vearswithOutas

    ;sistedreproductivetechnOlogies.Thepatemalr.elation

    ;shipbetweencontrolsubiectsandtheiroffspringwas ;cOnfirmedusingtheAmpF/STR.PrOfilerPluszVgOsitV

    ;deteminationsystem(App1iedBiosystems,FosterCitv, ;CA,USA).AUpatientsandcontrolsubjectsbelongedto ;theHannationaljtyinTaiwan,memajorethI1icgroupin ;China(makingupmorethan95%ofthisprovexalninati0n, ;atleasttwosemenanalyses,hormoneassays(1uinizing ;h0rmone[LH],f0uiclestimulatinghorn1one[FSH],pro

    ;1actinPRLandtestosterone[T),karyotypingandamo

    ;leculartestfl0rchr0mosoma1deleti0ns.Patientssus

    ;pectedtOhavenOn?Obsn1lctiVeazOOspeI111jawerleadVised ;tOundergobilateraltesticularbiOpsies.Serumlevels0f ;FSH,LH,PRLandTweremeasuredusingcOmmercial ;radiOimmunOassaVts:COatA.COumFSHIRMACOat

    ;ACOuntLHIRMA.COatACountPRLIRMAand

    ;MMI?ITETotalTest0sterone(DiagnosticProducts,Los ;Angeles,CA,USA1.ChrI)mOsomeanalVsiswasperfbm1ed ;usingtheGTGmethod(G_bandingbvTrvpsinGiemsa

    ;technique).MoleculLrana1vsisofY_chromosoma1dele

    ;tiOnsinc1udedacOmbinatiOn0fl6genebasedprimers,as

    ;describedpreviouslv34].Patientswimanvidentifiable ;causeofma1einfertilitV,includingcongenitalbilatera1ab. ;sence0fvasdeference(CBAVD1,crvotorchidism, ;varicOcele,diabetesmellitusOrhVpertension,0rwithhis

    0ryhatmayaftectspenaogenes1s(e.g.,0rChit1s,?Iauma,

    ;malignancies,.)wereexcludedfromthestudvgr0up.

    ;NOsignicantdifferencewasf0undbetweenage.serum ;LH.estradiOlandTconcentratiOnsOfinfertilemenand ;controlsubiects.SpermcountandFSHconcentrations ;weresignificantlVhigherinpatientscOmparedwiththe ;controlgr0up(P<0.005).0f20Ostudvsubjects,l37 ;hadseveI_eOlig0spemiaand63hadazOOspeImia. ;2.2SequencennnlsiSofpntients

    _plesofpatientsweresubjected ;GenomicDNAsaI1

    ;tOsequenceanalysisfOrtheentirecodingsequencesOf ;t