Expression of Wild-Type Rp1 Protein in Rp1 Knock-in Mice Rescues the Retinal Degeneration Phenotype 英文参考文献.docVIP

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Expression of Wild-Type Rp1 Protein in Rp1 Knock-in Mice Rescues the Retinal Degeneration Phenotype 英文参考文献.doc

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Expression of Wild-Type Rp1 Protein in Rp1 Knock-in Mice Rescues the Retinal Degeneration Phenotype 英文参考文献

ExpressionofWild-TypeRp1ProteininRp1Knock-in MiceRescuestheRetinalDegenerationPhenotype QinLiu1,RobW.J.Collin2,3,4,FransP.M.Cremers2,4,AnnekeI.denHollander3,4,L.Ingeborghvanden Born5,EricA.Pierce1* 1Berman-Gund Laboratory for the Study of Retinal Degenerations, Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America, 2Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, 3Department ofOphthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, 4Nijmegen Centre for Molecular Life Sciences, Radboud UniversityNijmegenMedicalCentre,Nijmegen,TheNetherlands,5TheRotterdamEyeHospital,Rotterdam,TheNetherlands Abstract Mutationsintheretinitispigmentosa1(RP1)geneareacommoncauseofautosomaldominantretinitispigmentosa(adRP), and have also been found to cause autosomal recessive RP (arRP) in a few families. The 33 dominant mutations and 6 recessiveRP1mutationsidentifiedtodateareallnonsenseorframeshiftmutations,andalmostexclusively(38outof39)are located in the 4th and final exon of RP1. To better understand the underlying disease mechanisms of and help develop therapeuticstrategiesforRP1disease,weperformedaseriesofhumangeneticandanimalstudiesusinggenetargetedand transgenic mice. Here we report that a frameshift mutation in the 3rd exon of RP1 (c.686delC; p.P229QfsX35) found in a patientwithrecessiveRP1diseasecausesRPinthehomozygousstate,whereastheheterozygouscarriersareunaffected, confirmingthathaploinsufficiencyisnotthecausativemechanismforRP1disease.WethengeneratedRp1knock-inmice withanonsenseQ662Xmutationinexon4,aswellasRp1transgenicmicecarryingawild-typeBACRp1transgene.TheRp1- Q662XalleleproducesatruncatedRp1protein,andhomozygousRp1-Q662Xmiceexperienceaprogressivephotoreceptor degeneration characterized disorganization of photoreceptor outer segments. This phenotype could be prevented by expressionofanormalamountofRp1pro