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不唯職稱論文范文1

遺傳性牙齦纖維瘤病（Hereditarygingivalfibromatosis，HGF）是一種較罕見(jiàn)口腔遺傳性疾病，有孤立和綜合征兩種發(fā)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(jìn)行性、彌漫性增生肥大，嚴(yán)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(qū)11cM的候選區(qū)域。為了進(jìn)一步方便克隆HGF的致病基因，我們收集了國(guó)內(nèi)5個(gè)HGF家系。利用2p21區(qū)域更精細(xì)的STRP標(biāo)記，將候選區(qū)域定位于D2S2144和D2S2163兩個(gè)位點(diǎn)之間，與Hart報(bào)道的候選區(qū)域有2.8Mb的重疊區(qū)。NCX1和CALM2過(guò)去一直被認(rèn)為是2個(gè)重要的疾病候選基因，現(xiàn)已被反射雜種制圖的結(jié)果排除在我們定位的候選區(qū)域之外。我們的CP突變篩選結(jié)果顯示，該候選區(qū)域另4個(gè)重要的候選基因CYP1B1、PRKR、PRKCN、FEZ2以及應(yīng)用Gecan、Genfinder和GRAIL預(yù)測(cè)出的功能與HGF相關(guān)的NCX1樣的基因都與HGF無(wú)因果關(guān)系。

此外，在收集的5個(gè)家系中，睢寧家系的所有患者都是在一周歲以內(nèi)患病，而其它家系都在2歲以后才開(kāi)始發(fā)病，因此我們稱之為早發(fā)性牙齦纖維瘤病。該家系的致病基因不與2p21的STR標(biāo)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(diǎn)之間。首次運(yùn)用家系連鎖分析的方法為HGF表型異質(zhì)性提供了分子遺傳學(xué)基礎(chǔ)。

牙本質(zhì)生成不全是一種常染色體顯性遺傳性疾病，其病因?yàn)檠辣举|(zhì)生成和礦化紊亂。最近，該病的致病基因的候選區(qū)域已從D4S2691-D4S26926.6cM的范圍縮小到GATA62A11-D4S15632.0Mb。我們利用國(guó)內(nèi)5個(gè)DGI-II大家系，將致病基因的候選區(qū)域進(jìn)一步縮小至800Kb。突變篩選試驗(yàn)的結(jié)果顯示，在淮陰家系中，D基因第三內(nèi)含子剪接位點(diǎn)的供位GT突變?yōu)锳T，在轉(zhuǎn)錄過(guò)程中可能導(dǎo)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(zhuǎn)換為TTT(V18F)。其它基因都沒(méi)有與DGI-II呈因果關(guān)系的突變，只是發(fā)現(xiàn)了一些編碼區(qū)的單核苷酸態(tài)（c）。但我們不能排除這些基因的內(nèi)含子和以及一些調(diào)節(jié)區(qū)可能存在的突變。800kb的區(qū)域相對(duì)較小、易于操作，因此我們構(gòu)建了覆蓋候選區(qū)域的BACcontigs，同時(shí)也構(gòu)建了候選區(qū)域高覆蓋率的BAC測(cè)序亞克隆庫(kù)，為建立候選區(qū)域的轉(zhuǎn)錄圖譜及測(cè)序提供了基礎(chǔ)。

關(guān)鍵詞：遺傳性牙齦纖維瘤病牙本質(zhì)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,