心房顫動機(jī)制研究進(jìn)展

--細(xì)胞核孔復(fù)合物與跨核運輸障礙.故事的開始：

常染色體隱性遺傳房顫家系1.-57familymembers-32males-25females-5livinggenerations-Age:3m-93y-Autosomalrecessiveinheritancepattern-7consanguineousmarriagesAnInterestingFamilyCirculation,2004.Obertietal.Circulation,2004;110:3753-3759ProbandV:11

-ChronicAF-QTc=0.42s-Deliveredbycaesareansectionduetofetaltachycardia,HRof250bpm,atrialfibrillationandatrialflutter-Echoatday2:markeddilatationofbothatria,EF52%-EPat1mdetectedAF,ablationofAVnode-PacemakerEchoat2m:mildatrialdilatation,normalEF52%-Diedsuddenlyat15m.Obertietal.Circulation,2004;110:3753-3759PatientVI:2-ChronicAF-QTc=0.40s-HR=125bpmwithdigoxinandpropafenoneEchoat15m:normal-Diedsuddenlyat19m.Obertietal.Circulation,2004;110:3753-3759PatientV:9-Atrialflutter-DeliveredbyCsectionduetofetaltachycardia-Bornwithsupraventriculartachycardia-ECGat24d:atrialflutter,HR=200bpm-Echoat24d:normal-LaterEcho:milddilatationofleftventricleandleftatria-Diedsuddenlyat3m.Obertietal.Circulation,2004;110:3753-3759PatientV:10-Bornwithatrialtachycardia-Echo:normal-Diedsuddenlyat2mPatientVI:1-Bornwithatrialtachycardia-Electricalconversionat20d-Echoat1m:normal-Diedsuddenlyat18mPatientVI:3-BornwithAFandatrialtachycardiaonFeb.14,2007-Insinusrhythmonpropafenone,propranolo,aspirinFamilymemberIV:17andIV:18:-diedsuddenly.是什么導(dǎo)致了此家系中早發(fā)、惡性房顫？2.連鎖分析Circulation,2004.NUP155突變R391H.NUP155核孔復(fù)合體（nuclearporecomplex）主要成分.核孔復(fù)合體負(fù)責(zé)大分子物質(zhì)在細(xì)胞核與細(xì)胞質(zhì)之間轉(zhuǎn)運mRNArRNAsnRNAtRNATranscriptionfactorsRNApolymeraseSplicingfactorsDNApolymeraseReplicationproteinsDNArepair,cellcycleproteinsChromatinproteinsRibosomalproteins.如何進(jìn)一步證實NUP155突變可以導(dǎo)致房顫？3.NUP155基因敲除小鼠NUP155-/-小鼠在胚胎期8.5天內(nèi)死亡NUP155+/-小鼠中NUP155蛋白的心肌表達(dá)量減半.NUP155

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小鼠陣發(fā)性房顫.InducedAFinNUP155+/-KOMiceWTNUP155+/-KOAFIrregularRR.NUP155突變?nèi)绾螌?dǎo)致房顫？4.影響Hsp70mRNA轉(zhuǎn)運出核---影響Hsp70蛋白質(zhì)轉(zhuǎn)運入核NUP155缺陷(突變與表達(dá)下調(diào))Hsp70Hsp70.心房肌細(xì)胞動作電位時長變短NUP155

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小鼠.WhatisthemechanismforAPDshorteninginNUP155+/-KOmice?★.IncreasedIK1CurrentinNUP155KOCardiomyocytes

.IncreasedKir2.1ExpressioninNUP155KOMice

.Stress.結(jié)論第一隱性房顫伴猝死基因發(fā)現(xiàn)第一次將核孔復(fù)合體聯(lián)結(jié)到心血管疾病關(guān)于非離子通道基因?qū)е路款澋牡谝粓蟮腊l(fā)現(xiàn)一嶄新的控制或治療房顫的藥靶核孔復(fù)合體蛋白NUP155突變可以在人和動物中導(dǎo)致房顫NUP155突變通過影響蛋白質(zhì)的核轉(zhuǎn)入及mRNA的核輸出導(dǎo)致房顫NUP155突變通過縮短心房細(xì)胞動作電位間期,可能引起reentry導(dǎo)致房顫NUP155突變通過增加Kir2.1表達(dá)和IK1鉀電流,縮短心房細(xì)胞動作電位間期.華中科大博士研究生張賢欽以第一作者在國際頂尖學(xué)術(shù)雜志

《Cell》發(fā)表論文《細(xì)胞》出版社專門做了新聞發(fā)布、世界幾百家媒體，包括美國，中國，日本，南韓，比利時等國新聞單位，都做了報道房顫與猝死致病新基因發(fā)現(xiàn).致謝華中科技大學(xué)生命科學(xué)與技術(shù)學(xué)院人類基因研究中心CARDIO-X團(tuán)隊教師：凃欣、石立松、任翔、柯鐵、李輝、李先濤博士生：李聰、王鵬云、汪樊、徐承啟、王楚楚李修春、王丹