Ablation of Whirlin Long Isoform Disrupts the USH2 Protein Complex and Causes Vision and Hearing Loss 英文参考文献.docVIP

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Ablation of Whirlin Long Isoform Disrupts the USH2 Protein Complex and Causes Vision and Hearing Loss 英文参考文献.doc

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Ablation of Whirlin Long Isoform Disrupts the USH2 Protein Complex and Causes Vision and Hearing Loss 英文参考文献

AblationofWhirlinLongIsoformDisruptstheUSH2 ProteinComplexandCausesVisionandHearingLoss JunYang1¤a*,XiaoqingLiu1,YunZhao1¤b,MichaelAdamian1,BasilPawlyk1,XunSun1¤c,D.Randy McMillan2,M.CharlesLiberman3,TiansenLi1¤c* 1The Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United StatesofAmerica,2DepartmentofPediatrics,UniversityofTexasSouthwesternMedicalCenter,Dallas,Texas,UnitedStatesofAmerica,3DepartmentofOtologyand Laryngology,HarvardMedicalSchoolandEaton-PeabodyLaboratory,MassachusettsEyeandEarInfirmary,Boston,Massachusetts,UnitedStatesofAmerica Abstract MutationsinwhirlincauseeitherUshersyndrometypeII(USH2),adeafness-blindnessdisorder,ornonsyndromicdeafness. The molecular basis for the variable disease expression is unknown. We show here that only the whirlin long isoform, distinctfromashortisoformbyvirtueofhavingtwoN-terminalPDZdomains,isexpressedintheretina.Bothlongandshort isoformsareexpressedintheinnerear.TheN-terminalPDZdomainsofthelongwhirlinisoformmediatestheformationofa multi-proteincomplexthatincludesusherinandVLGR1,bothofwhicharealsoimplicatedinUSH2.WelocalizedthisUSH2 proteincomplextothepericiliarymembranecomplex(PMC)inmousephotoreceptorsthatappearsanalogoustothefrog periciliaryridgecomplex.Thelatterisproposedtoplayaroleinphotoreceptorproteintraffickingthroughtheconnecting cilium.MicecarryingatargeteddisruptionneartheN-terminusofwhirlinmanifestretinalandinnereardefects,reproducing theclinicalfeaturesofhumanUSH2disease.ThisisincontrasttomicewithmutationsaffectingtheC-terminalportionof whirlin in which the phenotype is restricted to the inner ear. In mice lacking any one of the USH2 proteins, the normal localizationofallUSH2proteinsisdisrupted,andthereisevidenceofproteindestabilization.Takentogether,ourfindings provide new insights into the pathogenic mechanism of Usher syndrome. First, the three USH2 proteins exist as an obligatoryfunctionalcomplexinvivo,and