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不唯職稱論文范文1
遺傳性牙齦纖維瘤?。℉ereditarygingivalfibromatosis，HGF）是一種較罕見口腔遺傳性疾病，有孤立和綜合征兩種發病形式。其主要的遺傳方式為常染色體顯性遺傳。臨床特征為上下頜牙齦或全口牙齦呈慢性、進行性、彌漫性增生肥大，嚴重影響美觀和口腔功能。最近，該病的致病基因被定位于2p21區11cM的候選區域。為了進一步方便克隆HGF的致病基因，我們收集了國內5個HGF家系。利用2p21區域更精細的STRP標記，將候選區域定位于D2S2144和D2S2163兩個位點之間，與Hart報道的候選區域有2.8Mb的重疊區。NCX1和CALM2過去一直被認為是2個重要的疾病候選基因，現已被反射雜種制圖的結果排除在我們定位的候選區域之外。我們的CP突變篩選結果顯示，該候選區域另4個重要的候選基因CYP1B1、PRKR、PRKCN、FEZ2以及應用Gecan、Genfinder和GRAIL預測出的功能與HGF相關的NCX1樣的基因都與HGF無因果關系。
此外，在收集的5個家系中，睢寧家系的所有患者都是在一周歲以內患病，而其它家系都在2歲以后才開始發病，因此我們稱之為早發性牙齦纖維瘤病。該家系的致病基因不與2p21的STR標記連鎖，全基因組掃描和連鎖分析將該家系的HGF致病基因定位于5q13-q22的D5S1404和D5S1462兩位點之間。首次運用家系連鎖分析的方法為HGF表型異質性提供了分子遺傳學基礎。
牙本質生成不全是一種常染色體顯性遺傳性疾病，其病因為牙本質生成和礦化紊亂。最近，該病的致病基因的候選區域已從D4S2691-D4S26926.6cM的范圍縮小到GATA62A11-D4S15632.0Mb。我們利用國內5個DGI-II大家系，將致病基因的候選區域進一步縮小至800Kb。突變篩選試驗的結果顯示，在淮陰家系中，D基因第三內含子剪接位點的供位GT突變為AT，在轉錄過程中可能導致D基因第三外顯子的缺失；在南京家系中，D基因第一外顯子的最后一位密碼子CCA顛換為ACA(P17T)；在徐州家系中，D基因第二外顯子的第一位密碼子GTT轉換為TTT(V18F)。其它基因都沒有與DGI-II呈因果關系的突變，只是發現了一些編碼區的單核苷酸態（c）。但我們不能排除這些基因的內含子和以及一些調節區可能存在的突變。800kb的區域相對較小、易于操作，因此我們構建了覆蓋候選區域的BACcontigs，同時也構建了候選區域高覆蓋率的BAC測序亞克隆庫，為建立候選區域的轉錄圖譜及測序提供了基礎。
關鍵詞：遺傳性牙齦纖維瘤病牙本質生成不全-II型定位候選克隆
全基因組掃描連鎖分析
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,