◇论著◇小鼠10号染色体上致聋突变基因hml的精确定位QingyinZheng,BelindaSHarris,PatriciaFWard2Bailey,HepingYu,RoderickTBronson,MurielTDavisson,KennethRJohnson(TheJacksonLaboratory,BarHarbor,Maine04609,USA)摘要:目的定位小鼠致聋基因,识别决定其性状的有关突变,为人类耳聋基因研究提供动物模型。方法利用全基因组扫描来定位名为hml可致小鼠听力丧失突变基因。结果①hml基因定位在小鼠10号染色体上,距中心粒约43cM处。根据已知的鼠2人同源同线性特点,提示人的同源基因位于12q22-q24;②获得了25个多态性微卫星标记,通过高分辨的小鼠图谱将3个已知人类基因进行了正确排列,并将hml侯选基因限定在一个500kb的区域内。关键词:小鼠;耳聋;突变中图分类号:R764.21文献标识码:A文章编号:167128259(2004)0320209204Finemappingofadeafnessmutationhmlonmousechromosome10QingyinZheng,BelindaSHarris,PatriciaFWard2Bailey,HepingYu,RoderickTBronson,MurielTDavisson,KennethRJohnson(TheJacksonLaboratory,BarHarbor,Maine04609,USA)ABSTRACT:ObjectiveTomapamousedeafnessgene,identifytheunderlyingmutationanddevelopamousemodelforhumandeafness.MethodsGeneticlinkagecrossandgenomescanwereusedtomapanovelmutationnamedhypoplasiaofthemembranouslabyrinth(hml),whichcauseshearinglossinmutantmice.Results①hmlwasmappedonmouseChr10(～43cMfromthecentromere),suggestingthatthehomologoushumangeneison12q22-q24,whichwasdefinedonthebasisofknownmouse2humanhomologies(OMIM,2004).②Thisstudyhasgenerated25polymorphicmicrosatellitemarkers,placed3knownhumangenesinthecorrectorderinahigh2resolu2tionmousemapandnarrowedthehmlcandidategeneregiontoa500kbarea.KEYWORDS:mouse;deafness;mutationBiography:QingyinZheng(19632),MD,male,Researchscientist.Tel:+12072886609;Fax:+12072886149;Email:qyz@jax.org1Introduction1.1HereditaryhearingimpairmentinhumansandmiceGeneticimpairmentofhearingaffectsaboutoneofevery2000children1.Geneticanalysisofmousedeafnessmutationshasalreadyaidedintheidentificationofhumandeafnessgenes.Dependingongeneticbackgroundmutationsofonegenecancausere2cessiveordominant,syndromicornonsyndromichear2ingloss.Micehomozygousfortheshaker21mutation(sh1)arecharacterizedbycirclingbehavioranddeaf2ness.sh1wasshownbypositionalcloningtobeamu2tationoftheMyo7agene,whichencodesanuncon2ventionalmyosin2typeprotein2.Subsequently,thehomologousMYO7Ageneinhumanswasshowntoberesponsibleforbothdominant(DFNA11)andreces2sive(DFNB2)formsofhearingimpairment3,aswellasforUshersyndrometype1B4.1.2Hypoplasiaofthemembranouslabyrinth(hml)inmice,apotentialhomologyforhumandeafnessDFNA25Herewedescribeanewlydiscoveredmuta2tionthatcauseshearinglossinmice.ThemappositiononmouseChr10(～43cMfromthecentromere)sug2geststhatthehomologoushumangeneison12q222q24,onthebasisofknownmouse2humanhomologies(OMIM,2004).Adenovodeletioninasix2year2oldboywithcongenitalhearinglossaswellasmentalandmotorretardationprovidesapossiblehumanhomologuesyndromeofhmlatacriticalintervalto13cMinthe12q22-q24.1regionwhereDFNA25resides.Propor2第25卷第3期2004年6月西安交通大学学报(医学版)JournalofXiπanJiaotongUniversity(MedicalSciences)Vol.25No.3Jun.2004tionalsmallerbodysizerepresentsaphenotypesimilartohml.Thus,identificationofthehmlgenewillpro2videinsightintomolecularmechanismsofinnerearde2velopmentandformation.2Materialsandmethods2.1MiceandlinkagecrossHypoplasiaofthemembranouslabyrinth(hml)isarecessivesponta2neousmutationthataroseinacolonyofinbredBALB/cByJmiceatTheJacksonLaboratory(TJL),BarHar2bor,Maine.Homozygoushmlmicecanbeidentifiedat10daysofageby...
