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遗传性牙龈纤维瘤病（Hereditarygingivalfibromatosis，HGF）是一种较罕见口腔遗传性疾病，有孤立和综合征两种发病形式。其主要的遗传方式为常染色体显性遗传。临床特征为上下颌牙龈或全口牙龈呈慢性、进行性、弥漫性增生肥大，严重影响美观和口腔功能。最近，该病的致病基因被定位于2p21区11cM的候选区域。为了进一步方便克隆HGF的致病基因，我们收集了国内5个HGF家系。利用2p21区域更精细的STRP标记，将候选区域定位于D2S2144和D2S2163两个位点之间，与Hart报道的候选区域有2.8Mb的重叠区。NCX1和CALM2过去一直被认为是2个重要的疾病候选基因，现已被反射杂种制图的结果排除在我们定位的候选区域之外。我们的CP突变筛选结果显示，该候选区域另4个重要的候选基因CYP1B1、PRKR、PRKCN、FEZ2以及应用Gecan、Genfinder和GRAIL预测出的功能与HGF相关的NCX1样的基因都与HGF无因果关系。
此外，在收集的5个家系中，睢宁家系的所有患者都是在一周岁以内患病，而其它家系都在2岁以后才开始发病，因此我们称之为早发性牙龈纤维瘤病。该家系的致病基因不与2p21的STR标记连锁，全基因组扫描和连锁分析将该家系的HGF致病基因定位于5q13-q22的D5S1404和D5S1462两位点之间。首次运用家系连锁分析的方法为HGF表型异质性提供了分子遗传学基础。
牙本质生成不全是一种常染色体显性遗传性疾病，其病因为牙本质生成和矿化紊乱。最近，该病的致病基因的候选区域已从D4S2691-D4S26926.6cM的范围缩小到GATA62A11-D4S15632.0Mb。我们利用国内5个DGI-II大家系，将致病基因的候选区域进一步缩小至800Kb。突变筛选试验的结果显示，在淮阴家系中，D基因第三内含子剪接位点的供位GT突变为AT，在转录过程中可能导致D基因第三外显子的缺失；在南京家系中，D基因第一外显子的最后一位密码子CCA颠换为ACA(P17T)；在徐州家系中，D基因第二外显子的第一位密码子GTT转换为TTT(V18F)。其它基因都没有与DGI-II呈因果关系的突变，只是发现了一些编码区的单核苷酸态（c）。但我们不能排除这些基因的内含子和以及一些调节区可能存在的突变。800kb的区域相对较小、易于操作，因此我们构建了覆盖候选区域的BACcontigs，同时也构建了候选区域高覆盖率的BAC测序亚克隆库，为建立候选区域的转录图谱及测序提供了基础。
关键词：遗传性牙龈纤维瘤病牙本质生成不全-II型定位候选克隆
全基因组扫描连锁分析
MaingandcloningofHereditaryGingivalFibromatosis
andDentinogenesisimperfectatypeII
HereditaryGingivalFibromatosis(HGF)isanoralinheritablediseasecharacterizedbyaslowlyprogreiveenlargementofthegingivaltiuessurroundingboththemaxillaryandthemandibulardentitionwhichresultsinbothaestheticandfunctionalproblems.Recently,anautosomaldominantgingivalfibromatosislocuswasmaedtoan11cMintervalboundedbyD2S1788andD2S2298.Inordertorefinethepreviouslymaedregionandfacilitytheidentificationoftheunderlyinggenesreoibleforthedisorder,wecollectedfivehereditarygingivalfibromatosisfamilieswhichweretypedbyuseofpolymorphicmarkerson2p21.Inthefourfamilies,thegingivalfibronmatosislocuswaslocatedtoanaroximately8.7cMregionon2p21whichoverlaby2.8Mbwithpreviouslymaedinterval.
High-resolutionradiationhybridmaingshowedthattwoimportantgenes,CALM2andNCX1whichpreviouslymaedtoHGFcandidateintervalwereoutsideoftheHGFcriticalregion.CPanalysisandsequencingofcodingregionofcandidategenesCYP1B1,PRKR,PRKCN,PEZ2andtheotherrelevantgene(NCX-like)whichwaspredictedbyGECAN,GENFINDERandGRAILfailedtorevealanydisease-ecificmutatioinaffectedindividualsandnormalcontrols,suggestingthatmutatiointhesegenesmaynotplayacausativeroleinthepathogenesisofdisorder.
Allaffectedindividualsinthefifthfamily(pedigree)begantheirgingivalenlargementwithinoneyearold.OtherHGFfamiliestookoetaftertwoyearsold.Sowecalledthepedigreeas“early-oettype”HGF.ThepedigreeHGFlocusdidnotcosegregatewiththeATRmarkerson2p21.Usingagenomewidesearchstrategyandlinkageanalysis,weidentifiedanewgeneticlinkage(Zmax=4.81θ=0.00)atapositionof111.97cMbetweenD5S1462andD5S1721fortheHGFphenotypetopolymorphicmarkersinthegeneticregionofchromosome5q13-q22.HaplotyperecotructionestablishedthecentromericboundarytoD5S1491,andthetelomericboundarytoD5S1453aumingcompletepenetranceandnophenocopy.
DentinogenesisimperfectatypeIIisanautosomaldominantdisorderofdentinformationandmineralization.Recently,thecriticalregionhasbeennarrowedfromthe6.6cMD4S2691-D4S2692intervaltothe2.0MbGATA2A11-D4S1563intervalathumanchromosome4q21.Inthecurrentinvestigation,fiveexteiveChineseDGI-IIpedigreeswerecollected.LinkageanalysiswithSTRPat4q21regionhasfurtherrefinedthecandidateregiont oa800Kbinterval.Theresultsofthemutation-screeningaaywithPCR-CPandsequenceofDgenehavedemotratedthataGtoAtraitionwasdetectedinthedonorlicesite(GT)ofintron3inHYpedigree.InNJfamilyallaffectedmemberscarryaCCAtoACAtraversionatcondon17(P17T).AGtoTtaversationinthefirstnucleotideofexon2wasidentifiedinaffectedindividualsofXZfamily.OthergenesincriticalregionhavebeenexcludedfromacausativeroleinthepathogenesisofDGI-II.Theseresultshoweverdonotexcludemutatioinotherfamiliesoroccurredinnon–codingandregulationalregioofthesegenes,the800Kbcriticalregionisaneasilymanipulatedfragment.Therefore,theBACcontigsaingthecriticalintervalwerecreatedandcotructionofBACsequencingsubclonelibraryhasbeenfinished.TheworkwillprovetobeacentralrecourceinthecreationofatracriptionmapandthesequenceoftheregionandwillaidintheultimatecloningoftheDGI-IIlocusinotherDGI-IIoftheregionandwillaidintheultimatecloningiftheDGI-IIlocusinotherDGI-IIfamilies,