NovelMutationsintheConnexin26Gene(GJB2)ResponsibleforChildhoodDeafnessintheJapanesePopulationTakayukiKudo,1,2*KatsuhisaIkeda,1ShigeoKure,2YoichiMatsubara,2TakeshiOshima,1Ken-ichiWatanabe,1TetsuakiKawase,1KuniakiNarisawa,2andTomonoriTakasaka11DepartmentofOtorhinolaryngology,HeadandNeckSurgery,TohokuUniversitySchoolofMedicine,Sendai,Japan2DepartmentofMedicalGenetics,TohokuUniversitySchoolofMedicine,Sendai,JapanMutationsintheconnexin26gene(GJB2),whichencodesagap-junctionproteinandisexpressedintheinnerear,havebeenshowntoberesponsibleforamajorpartofnonsyn-dromichereditaryprelingual(early-child-hood)deafnessinCaucasians.Wehavese-quencedtheGJB2genein39Japanesepa-tientswithprelingualdeafness(group1),39Japanesepatientswithpostlingualprogres-sivesensorineuralhearingloss(group2),and63Japaneseindividualswithnormalhearing(group3).Threenovelmutationswereidentifiedingroup1:asinglenucleo-tidedeletion(235delC),a16-bpdeletion(176-191del(16)),andanonsensemutation(Y136X)infiveunrelatedpatients.The235delCmutationwasmostfrequentlyob-served,accountingforsevenallelesin10mutantalleles.Screeningof203unrelatednormalindividualsforthethreemutationsindicatedthatthecarrierfrequencyofthe235delCmutationwas2/203intheJapanesepopulation.Nomutationwasfoundingroup-2patients.Wealsoidentifiedtwonovelpolymorphisms(E114GandI203T)aswellastwopreviouslyreportedpolymor-phisms(V27IandV37I).GenotypingwiththesefourpolymorphismsallowednormalJapaneseallelestobeclassifiedintosevenhaplotypes.All235delCmutantallelesiden-tifiedinfourpatientsresidedonlyonhap-lotypetype1.ThesefindingsindicatethatGJB2mutationsarealsoresponsibleforprelingualdeafnessinJapan.Am.J.Med.Genet.90:141–145,2000.©2000Wiley-Liss,Inc.KEYWORDS:connexin26;GJB2;prelin-gualdeafness;mutation;polymorphism;JapaneseINTRODUCTIONHearinglossisthemostfrequentinheritedsensorydisorderinhumans,andinheriteddeafnesscanbeclassifiedasnonsyndromicorsyndromicdeafness.Nu-merousloci(∼50)fornonsyndromicdeafnesshavebeenfoundinthelast5years[VanCampandSmith,1999].Recentprogressinresearchondeafnessgenesrevealed13differentgenesfornonsyndromicdeafness[Avra-ham,1998;Kubischetal.,1999;Yasunagaetal.,1999].TheGJB2geneencodestheconnexin(Cx)26mol-ecule,whichisacomponentofthegapjunctions.Gapjunctionsconnectadjacentcells,allowingsmallmol-eculestopassfromonetothenextandexistingontheepithelialsupportingcellssurroundingthesensoryhaircellsofthecochleaandthefibrocytesliningthecochlearduct[Kikuchietal.,1995].TheGJB2genewasthefirsttobeassociatedwithautosomalrecessivenonsyndromicsensorineuraldeafness[Kelselletal.,1997].Todate,anumberofGJB2mutationshavebeendescribedintheMediterraneanEuropean[Zelanteetal.,1997],Israeli-Arab[Carrasquilloetal.,1997],American[Kelleyetal.,1998],andAshkenaziJewishpopulations[Morelletal.,1998],indicatingthatGJB2mutationsareremarkablycommonasacauseofupto50%ofprelingual(early-childhood)deafnessinthesepopulations.A30delGmutation(alsoknownas35delG)wasidentifiedtobeparticularlycommonintheEuropeanandAmericanwhitepopulations[Zelanteetal.,1997;Estivilletal.,1998].However,asnosuchmutationhasbeenfoundintheAsianorblackpopulations,thesignificanceofGJB2mutationsinJapanesepatientshasremainedunknown.Weexaminedprelingualdeafnesspatients,postlin-gualsensorineuralhearingloss(SNHL)patients,andnormalindividualsintheJapanesepopulationbydi-rectsequencingoftheGJB2gene.Wealsodeterminedahaplotype...
