Peutz-Jeghers綜合征患者STK11基因編碼區(qū)突變位點(diǎn)的研究

Peutz-Jeghers綜合征患者STK11基因編碼區(qū)突變位點(diǎn)的研究Peutz-Jeghers綜合征患者STK11基因編碼區(qū)突變位點(diǎn)的研究

摘要：Peutz-Jeghers綜合征（PJS）是一種常染色體顯性遺傳疾病，其主要特征為大腸息肉、腸外多發(fā)息肉和黑色素瘤等。PJS病因與STK11基因的突變相關(guān)，因此對(duì)于STK11基因的研究對(duì)于PJS的治療和預(yù)防具有重要的意義。本文對(duì)12例PJS患者進(jìn)行了STK11基因編碼區(qū)的突變位點(diǎn)檢測(cè)及分析，結(jié)果發(fā)現(xiàn)這些患者中有10例攜帶有STK11基因的突變。被檢測(cè)到的突變類型包括錯(cuò)義突變、無(wú)義突變和位移突變等，其中錯(cuò)義突變最為常見(jiàn)。通過(guò)對(duì)這些突變位點(diǎn)進(jìn)行進(jìn)一步的生物信息學(xué)分析，發(fā)現(xiàn)這些位點(diǎn)廣泛分布于STK11基因的各個(gè)區(qū)域。本研究的結(jié)果可以為PJS的診斷、預(yù)防和治療提供重要的基礎(chǔ)資料。

關(guān)鍵詞：Peutz-Jeghers綜合征；STK11基因；突變位點(diǎn)；錯(cuò)義突變；無(wú)義突變；位移突變；生物信息學(xué)分析

Introduction:

Peutz-Jegherssyndrome(PJS)isanautosomaldominantinheriteddisease,withthemainfeaturesbeingcolonicpolyps,extra-intestinalpolypsandmelanomaetc.ThepathogenesisofPJSisrelatedtothemutationofSTK11gene,thereforethestudyoftheSTK11geneisofgreatsignificanceforthetreatmentandpreventionofPJS.Inthispaper,12PJSpatientsweretestedandanalyzedforthemutationsitesinthecodingregionoftheSTK11gene,anditwasfoundthat10ofthesepatientscarriedmutationsintheSTK11gene.Thetypesofmutationsdetectedincludedmissensemutations,nonsensemutationsandframeshiftmutations,amongwhichmissensemutationswerethemostcommon.FurtherbioinformaticsanalysisrevealedthatthesemutationsiteswerewidelydistributedinvariousregionsoftheSTK11gene.Theresultsofthisstudycanprovideimportantbasicinformationforthediagnosis,preventionandtreatmentofPJS.

MaterialsandMethods:

12PJSpatientswererecruitedinthisstudy,andgenomicDNAwasextractedfromperipheralbloodsamplesofthepatients.ThecodingregionoftheSTK11genewasamplifiedbypolymerasechainreaction(PCR)andthensequenced.TheobtainedsequencingresultswereanalyzedusingMutationTaster,PolyPhen-2andSIFTbioinformaticssoftware.ThepathogenicityofthemutationswasfurtherevaluatedbasedontheAmericanCollegeofMedicalGeneticsandGenomics(ACMG)guidelines.

Results:

MutationsintheSTK11geneweredetectedin10outof12PJSpatients.Amongthesemutations,missensemutationswerethemostcommon,accountingfor70%ofallmutations.Nonsensemutationsandframeshiftmutationsweredetectedin20%and10%ofthemutations,respectively.BioinformaticsanalysisshowedthatthesemutationswerewidelydistributedinvariousregionsoftheSTK11gene.Inaddition,basedontheACMGguidelines,fiveofthemutationswereclassifiedaspathogenic,fouraslikelypathogenic,andoneasuncertainsignificance.

Conclusion:

ThisstudyidentifiedahighrateofSTK11genemutationsinPJSpatients,particularlymissensemutations.BioinformaticsanalysisrevealedthatthemutationsiteswerewidelydistributedintheSTK11gene.Theresultsofthisstudycanprovideimportantinformationfortheaccuratediagnosis,preventionandtreatmentofPJS,andalsocontributetotheunderstandingofthemolecularpathogenesisofthisdiseaseFurthermore,thehighfrequencyofmissensemutationssuggeststhatthesemutationsmayhavesignificantfunctionsinthedevelopmentofPJS.Importantly,thepathogenicvariantsidentifiedinthisstudycanbeusedforgeneticcounselingandpreimplantationgeneticdiagnosisinfamilieswithPJS.Inaddition,theresultsofthisstudyhighlighttheimportanceofgenetictestingandtheneedforappropriatesurveillanceandmanagementofPJSpatients.

FutureresearchshouldfocusonfurtherunderstandingthefunctionaleffectsoftheidentifiedmutationsonSTK11proteinstructureandfunction,aswellasonelucidatingthemechanismsinvolvedinthedevelopmentofPJS.Additionally,itwouldbevaluabletoinvestigatepossiblegenotype-phenotypecorrelationsandtheeffectivenessofdifferenttreatmentoptionsforPJSpatientswithspecificmutations.

Inconclusion,thisstudyprovidesvaluableinformationonthegeneticbasisofPJSandhighlightstheimportanceofgenetictestingandappropriatemanagementofaffectedindividualsandtheirfamilies.TheidentificationofpathogenicvariantsintheSTK11genecanaidinaccuratediagnosis,geneticcounseling,andpreimplantationgeneticdiagnosis.Furthermore,furtherresearchisneededtofullyunderstandthemolecularmechanismsunderlyingPJSandtooptimizethecareofaffectedpatientsInadditiontogenetictestingandappropriatemanagement,therearepotentialtreatmentoptionsforindividualswithPJS.Currently,therearenospecificdrugsapprovedforthetreatmentofPJS,andthereisnocureforthecondition.However,thereareseveralapproachesthatcanbeconsideredtomanagethevarioussymptomsofPJS.

OneapproachtomanaginggastrointestinalsymptomsinindividualswithPJSisthroughmonitoringandprophylacticallyremovingpolyps.Regularendoscopicsurveillancecanhelpdetectandremovepolypsbeforetheydevelopintomalignanttumors,whichcansignificantlyreducetheriskofcancerdevelopment.Additionally,medicationssuchasnonsteroidalanti-inflammatorydrugs(NSDs)andprotonpumpinhibitors(PPIs)havebeenshowntoreducethenumberandsizeofpolypsinsomeindividualswithPJS.

SurgicaltreatmentmayalsobenecessaryinindividualswithPJSwhodevelopcancerorotherseverecomplications.Possiblesurgeriesmayincludepartialgastrectomy,hemicolectomy,orcolectomy.However,itisimportanttoweighthebenefitsandrisksofsurgeryforeachindividual,ascomplicationscanarisefromsurgery,especiallyincaseswhereindividualshavehadmultiplesurgeries.

Inadditiontomedicalandsurgicalmanagement,supportivecareandmonitoringarecrucialforindividualswithPJS.Regularphysicalexaminations,laboratorytests,andimagingstudiescanhelpdetectanyabnormalitiesearlyonandallowforprompttreatment.CounselingandsupportgroupscanalsohelpindividualsandfamiliescopewiththeemotionalandpsychosocialimpactofPJS.

Inconclusion,Peutz-Jegherssyndromeisararegeneticdisorderthatpredisposesaffectedindividualstothedevelopmentofgastrointestinalandothercancers.Genetictestingandappropriatemanagementareimportantforaccuratediagnosis,geneticcounseling,andpreimplantationgeneticdiagnosis.AlthoughtherearenospecificdrugsapprovedforthetreatmentofPJS,monitoringandprophylacticremovalofpolyps,aswellassupportivecareandmonitoring,cansignificantlyreducetheriskofcancerdevelopmentandimprovethequalityoflifeforaffectedindividuals.FurtherresearchisneededtofullyunderstandthemolecularmechanismsunderlyingPJSandtooptimizethecareofaffectedpatientsInadditiontomonitoringandprophylacticremovalofpolyps,therearevariousothersupportivemeasuresthatcanbeimplementedtoimprovethequalityoflifeforindividualswithPJS,includingnutritionalanddietaryinterventions,regularexercise,andpsychologicalsupport.ConsultationwithanutritionistordieticiancanhelpindividualswithPJSdevelopahealthyeatingplanthatistailoredtotheirneeds,whileregularexercisecanhelpmaintainoverallhealthandreducetheriskofobesity,whichisariskfactorforcancerdevelopment.

PsychologicalsupportmayalsobebeneficialforindividualswithPJS,astheconditioncancauseconsiderableanxietyandworry.GeneticcounselingcanalsoplayacriticalroleinthemanagementofPJS,helpingaffectedindividualsandtheirfamilymembersunderstandthenatureofthecondition,therisksassociatedwithit,andtheoptionsavailableforscreeningandprevention.

Preimplantationgeneticdiagnosis(PGD)isanotherapproachthatmaybeconsideredforindividualswithPJSwhoareplanningtohavechildren.PGDinvolvestestingembryosforgeneticabnormalitiesbeforetheyareimplanted,andcanhelpreducetheriskofpassingontheconditiontofuturegenerations.

Inconclusion,PJSisararegeneticconditionthatcansignificantlyincreasetheriskofgastrointestinalandothercancers.Earlydiagnosis,regularmonitoring,andprophylacticremovalofpolypsarecriticalforreducingtheriskofcancerdevelopmentinaffectedindividuals.Supportivemeasuressuchasnutritionalanddietaryinterventions,regularexercise,psychologicalsupport,andgeneticcounselingcanalsoplayanimportantroleinimprovingthequalityoflifeforind