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Some Clinical and Molecular Aspects of Hemoglobinopathy Detected by Our Screening Test for the Past 11 Years

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SomeClinicalandMolecularAspectsofHemoglobinopathyDetected

byOurScreeningTestforthePastllYears KazuoHIDAKAandIwaolUCHI D"α〃"ze"tqrBiOc"e"zis"y,KZzz《ノas雄j〃ど(ガazIS℃〃ooA K"7tzs"hi7DZ-OZ,たりa?z (Rece"edo犯鋤""z6e?'3QZ994ノ Abstract Ahemoglobinopathysurveytotalingl70,000specimenswascarriedoutforthepast elevenyearsinfourcitieslainonthecoastofSetolnlandSeafroml979tol989. Nineteenvariantsofabnormalhemoglobinweredetectedandfourofthesewere noteworthytodepictbecauseoftheinstancesofahomozygogousHbTakamatsu,the notablechangephysico-chemicalnatureofHbNunobikiandhighoxygenaffinityofHb SyracuseandHbFukutomi. 65 Introduction Ahemoglobinopathysurveyhavebeenenforcelyconductedbyusinfourcitieslain onthecoastofSetolnlandSea,namely,Takamatsu,Kobe,FukuyamaandOkayama forthepastelevenyearsfroml979tol989.Intotalofl70,OOOspecimens,19kindsof abnormalhemoglobin(abnHb)weredetected.Thepresentpaperaimstodescribefour abnHbswhicharecharacteristicclinicallyandfunctionally. MaterialsandMethods Analiquot(2.0ml)ofwholebloodforhematologicalexaminationwasstoredina refrigerator(4℃)intheclinicallaboratorydepartmentinthetheKagawaCentral Hospital(Takamatsu),theKobeCentralCityHospital(Kobe),theFukuyamaNational Hospital(Fukuyama)andtheKawasakiHospital(Okayama) Theywerethentransportedonceaweekinanicecooledcontainertoour laboratory.Thenthespecimenstobescreenedwerepickedupbyemployingthe criteriaofage,sexandfullnameofindividualbyuseofacomputer. WhenanabnHbwasdetectedbyourconventionalisoelectricfocusing(IEF)on polyacrylamideslabgels(1),hematologicalandphysicalexaminationofthecarrierand familystudieswereinformedusfromthelaboratory. ThenthefollowingtestswerecarriedouttocharacterizetheabnHb,namely,

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ForstructuralanalysisofalltheabnHbs,determinationoftheaminoacidsubstitution intheaberrantchainandtheaminoacidsequencingofpeptidebyEdman'sstepwise methodwereperformed(5). ろ

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妬 KawasakilkaishiArts&Sci(20)1994 Resultanddiscussion NineteenvariantsofabnHbwereidentifiedfortheelevenyears.Thesewere classifiedaccordingtotheirnatureasshownintablel.OftheseabnHbs,fourspecific Hbvariants,namely,HbTakamatsu(HbTa),HbSyracuse(HbSy),HbNunobiki(Hb Nu)andHbFukutomi(HbFu)aredescribedastherepresentatives. Table、1.ClassificationofabnormalHbaccordingtocharacteristics 1abnHbdetectedintherestrictedarea HbTakamatsu,HbYusa,HbMizushi,HbFukuyama 2rarebutwidelydistributedabnHbinJapan HbUbe-2 3rareandfunctionallyabnHb HbSyracuse,HbNunobiki,HbFukutomi 4rareandstableabnHb HbJBangkok,HbGSzuhu,HbSt.Lukes,HbUmi HbRiyadh,HbGCousha廿a,HbAnkara,HbHanda HbJHabana,HbAlbany-Suma,HbHoshida, 1)HbTakamatsu('120Lys->Gln). ThefirstcaseofthisHbvariantintheTakamatsuareawasfoundinl979(6,7). SincetheneighteenadditionalHbTakamatsufamilieswithoutapparentconsanguinity ineachfamilyhavebeendetectedinthisareaandtheyweredistributedover mountainousarearatherthanintheseacoastofKagawaprefecture.Oneindividualof familylofheterozygousHbTakamatsuwasthecommonpersonbymarrigewiththat offamily6.Accordingly,oneofhistwodaughtershappenedtobebornasa homozygoteforthisHbvariantbyafamilystudy.Shewasthefirsthomozygotefor む aHbvariantfoundintheJapanese.Shewasal2year-oldwhowaswell-developed, well-nourishedandhadnoparticularabnormalitiesinherphysicalexaminationsatthe timeofdiscovery. Sheshowedneitherhematologicalabnormalitynorhemolytic tendencies(RBC4.04xlO'2/1,Hbl1.89/dl,PCVO351/1,MCV87fl,MCHC3349/dl, WBC4.3xlO9/1,serumbilirubinwithinnormallimits,serumiron84"g/dlandserum TIBC331"g/dl)IsoelectricfocusingofherhemolysateshowedonlytwobandsofHb TakamatsuandHbAzandtheirproportionwas97.8and2.2%,respectivelyHbFwas 0.8%byalkalinedenaturation.TheoxygenequilibriumcurveforthepurifiedHb TakamatsuwasthesameasthatmeasuredforHbA.StructuralanalysisofHb Takamatsushowedthatalysineatl20positionoffchainwasreplacedbya glutamine. HbTakamatsuisharmlesstothecarrierandisextremelystableabnormalHb,as shownbythepresenceofthehealthyhomozygote.Therefore,itisconsideredthatHb Takamatsumightbeoriginatedfromasinglecommonancestoranddistributedina highfrequencywithoutanaturalselectioninthesamearea.

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6 7 KazuoHIDAKAetal:Someclinicalandmolecularaspectsofhemoglobinopathy 2)HbSyracuse(m43His→Pro)(8) Theproposituswasa22year-oldfemalewhowasadmittedtothehospitalfor rhinitisinSep.,1981.Herhematologicexaminationrevealedpolycythemiawithout cyanosis(RBC6.29xlO'2/1,Hb15.89/dl,PCV0.521/1,MCV83fl,MCH24.2p9,MCHC 29.69/dl,reticulocytelO%,serumbilirubinO6mg/dl).Shewashospitalizedagain,by complainingofpyelitisinDec.,1981.Herpolycythemiawasstillevident.InlEFofher hemolysate,HbSyracusedemostratedfast-movingbutveryclosetoHbA. Successfulseparationofthesetwobandswas,therefore,achievedonlybylEF.The otherelectrophoreticmethods,suchascelluloseacetatemembrane,agargel,agarosegel andstarchgel,wereperformedinvain.HbSyracuseconstituted41.4%ofthetotalHb inlEF.TheresultoftheoxygenequilibriumcurveofHbSyracuseat25℃showeda highoxygenaffinity,showingthefollowingvalueoflogP50=-0.01(HbA=1.02)and-0.14(HbA=0.85)atpH7.0and74,respectively.Theheme-hemeinteraction,alkaline Bohreffectand2,3-DPGeffectofHbSyracusewerealsomarkedlydecreasedas indicating:Hill'sn=1.23(HbA=2.54)and1.24(HbA=2.77)atpH7.0and7.4, respectively,thealkalineBohreffect=-0.33(HbA=-0.44)andthe2,3-DPGeffect=0. 09(HbA=0.14).SequenceanalysisofHbSyracuserevealedthattheProresiduewas

substitutedfortheHisresidueatpositionl43ofthePchain.IndeoxyHbstructure(T

structure),TheC-terminalHis(F146)formstwosaltbridges;namely,carboxylgroupis linkedtothee-aminogroupof"40Lys,whileitsimidazolegroupislinkedtothe carboxylgroupoff94Asp.Inaddition,B143Hisplaysanimportantroleforthe bindingof2,3-DPGandalsotheformationofsaltbridgebetween'146HisandB94AsP contributesabout50percenttothenormalalkalineBohreffect(9,10).InHbSyracuse, thesubstitutedProdisruptstheHhelixatpositionl43oftheC-terminalendofthe'

chainandthesesaltbridgesdescribedaboveareimpairedbytheco㎡ormational

alterationandthestabilityoftheTstructurewouldbeweakened,makingtheR

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bothBohreffectand2,3-DPGeffect.Theauto-oxidationvelocityofHbSyracusewas

slightlybutsignificantlyslowerthanthatofHbA.AccordingtoWallance(11),the

formationofmetHbbyauto-oxidationbeginswiththedissociationoftheoxygen moleculefromfullyligandedHb(oxyHb),followedbytheoxidationofdeoxyHbby freeoxygenatlowpHthatleadstotheformationofmetHbandsuperoxideanionas shownbelow. HbFe2+(02)−−→HbFe2++O2 HbFe2++02-−→metHbFe3++OZ

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Becauseofthedifferenceinoxygenaffinity,reaction(1)mayproceedmoreslowly inHbSyracusethaninHbA.Consequently,therateofauto-oxidationofHbSyracuse

maybelessthanthatofHbA.Likewise,itniaybepossibletoexplaintherateof

auto-oxidationofotherHbvariants,HbNunqbikiandHbFukutomi,becauseofhaving highoxygenaffinity. L 一 一

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6B KawasakilkaishiArts&Sci(20)1994 3)HbNmlobiki(141Arg→Cys)(12) Theproposituswasa44year-oldmalewhowasadmittedtothehospitalfor surgeryforacuteulcerativecolitis.Hishematologicalexaminationbeforesurgical operationindicatedanincreasedleukocytecountandslightanemia,butnotendency towardhemolrticane㎡a.Aftertheoperation,heshowedatendencytopolycythemia: RBC5.31xlO'2/1,Hbl6.19/dl,PCV46.51/1,MCV88fl,MCH30.3p9,MCHC34.6 9/dl,WBC7.7xlO9/1,platelet211xlO'0/1,Retic.0.9%.IEFofhishemolysaterevealed discretebandsofHbNunobiki,HbAandHbA2inthatorderfromtheanodetothe cathode. HbNunobikiconstituted13.1%ofthetotalHbandHbFwasO.95%.Theoxygen

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Pso=0.360(HbA=1.080)and0.223(HbA=0.900)atpH7.0and7.4,respectively.The heme-hemeinteraction,alkalineBohreffectand2,3-DPGeffectofHbNunobikiwere alsomarkedlydecreased,namely,Hill'sn=1.25(HbA=2.88)and1.23(HbA=2.77)at pH7.0and7.4,respectively,alkalineBohreffect=-0.34(HbA=-0.45)and2,3.PG

effect=0.060(HbA=0132).Theauto-oxidationrateofHbNunobikiwasremarkably

slowerthanthatofHbA.StructuralanalysisofHbNunobikiwasperformedas

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chain.Oneextraspotwasclearlyseenascomparedwiththefingerprintfromthe

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whentheseparatedHbNunobikiwasstoredforonemonthat4℃.itmovedmore

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chargethanHbA.ItwasobviousthattheSatomofthethiol(-SH)inCyswas

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HbNmobiki.ButHbPortAlegre("9Ser→Cys)andHbTa-li(B83Gly→Cys)allow

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4)Hb The gastritis、 Fukutomi(126Asp→Val)(13)

proposituswasa53year-oldmalewithlivercirrhosisandhemorrhagic

Theresultsofroutineanalysissuggestedaslighterythrocytosisinthepresence 凸

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ofhemorrhageandlatentjaundiceduetoliverdysfunction:RBC4.3xlO'2/1,Hb15.29/ dl,PCV0.451/1,WBC60xlO9/1,MCV104fl,MCH35.5p9,MCHC34.19/dl, gammaglutamyltranspeptidasel611U/1,totalbilirubin1.8mg/dl Hehasnosiblingsandhisparentsaredeceased.IEFofhishemolysate demonstratedthepresenceofHbsA,Fukutomi,A2andFukutomi-A2andtheseHbs amountedto72.7,24.4,2.2and0.7%ofthetotalpigmentintheorderdescribed.The reversedphaseHPLchromatogramofthetrypticdigestoftheafFuchainshowedan extrapeptide(QwT-13),whichjoinedcorefractionofthenormalchainasshowninfigurel. ThisfindingsuggestedthatthestructuralanomalywaslocatedbetweenafT-12and

QfT-13inthecoreregion.TwofragmentslabeledAandBwerepresentinthereversed

phaseHPLchromatogramofthechymotrypticdigestoftheoxidizedafFucoreobtained

byperformicacidoxidation.

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4 6 E匡吾︻国四・二乏邑壁つめ国宝 3 ロ ロ 。 7 7.8 13 1 14

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20 Elutionof Notethat 0 Fig.1 4 0 6 0 8 0 m i n trypticdigestof"chainofHbFukutomi. theafT-13peptideappearsasanextrapeak. TheresultofaminoacidanalysisofthesefragmentsdemonstratedanAsp-→Val substitutionatpositionl26.ThesequenceAsp-Lys(126-127)inthenormal"T-12 peptideiswellknowntoresisttotrypsindigestionbecausetheacidicasparticacidis closetothebasiclysine.Therefore,afT.13isusuallybelongstothetrypsin-resistant coreoftheafchain.However,whenthesequnceischangedtoVal-LysasinHb Fukutomi,C_terminalendofthelysineresidueiscleavedbytrypsinintheusualway. Therefore,theaberrantaJT-13peptideappearstogetherwithallothersolublepeptides. TheoxygenequilibriumcurveforthepurifiedHbFukutomirevealedamarkedly increasedoxygenaffinityandadecreasedheme-hemeinteractionascomparedtothe purifiedHbAinparentheses:logP50=0.201(HbA=1.084)and0.087(HbA=0.970)at pH7.0and7.4,Hill'sn=164(HbA=2.58)and1.92.(HbA=2.91)atpH7.0and7.4, respectively.TheHillplotoftheoxygenequlibriumofHbFukutomishowedthe

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KawasakilkaishiA、s&Sci(20)1994 7り biphasicnatureoftheoxygenaffinity,butthecauseofitcouldnotbeelucidated (figure2). |H Y S9'b 100− log A −矛一 〆 7 . 0 F u k u 亡 O m i 7 . 0 Fukutomi 9 A 00,0合99fQFI9I9JjI8IIjJIIf 0.5 0 5 0 -0.5 O ユ・010g恥2 0 0 1 . 0 2 . 0 1 0 g P o 2 OxygenequilibriumcurvesofpurifiedHbFukutomiandHbA. TherightsectionshowstheHillplotobtainedfromthesecurves atpH7.0 Fig.2. ThehemoglobinmoleculemodelofPerutz(14)suggests,inthedeoxyhemoglobin form(Tstructure),thecarboxylgroupoftheC-treminalArgofthecrchain(QI1)is linkedtothee-aminogroupofthel27Lysofitspartner"chain("2)andthe guanidiumgroupofArgataf1141isdirectedtowardtheaf-carboxylgroupofAspat af2126andtotheaf-aminogroupofValat"1viaaninterveningchlorideion.The forrnationoftheseioniclinkagemightbeinterruptedinthe"Nunobikisubunithaving C-terrninalCysinsteadofArgandinthe"FukutomisubunithavingValinsteadofAsp ataf126.Asaresult,thestabilityofTstructurewouldbeweakenedandthatofthe Rstructurewouldbestrengthenedasischaracteristicofhighoxygenaffinity. HbJBangkok,HbGSzuhu,HbGCoushatta,HbAnkara,HbHabanaandHb Albany-SumaweredetectedinTakamatsuandKobearea.Thesetwocitieshavebeen prosperoussinceancienttimes.Therefore,itisthoughtthatavariformabnormalHb whichisnotracialwasfoundasexpected. 一■ ●の ThisstudywassupportedinpartbyaResearchProjectGranttoll.(No.5-102) fromKawasakiMedicalSchool.

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