2022
XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice
Krappitz M, Bhardwaj R, Dong K, Staudner T, Yilmaz DE, Pioppini C, Westergerling P, Ruemmele D, Hollmann T, Nguyen TA, Cai Y, Gallagher AR, Somlo S, Fedeles S. XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice. Journal Of The American Society Of Nephrology 2022, 34: 110-121. PMID: 36270750, PMCID: PMC10101557, DOI: 10.1681/asn.2021091180.Peer-Reviewed Original ResearchConceptsPolycystin-1Polycystin-2Functional polycystin-1Amino acid substitution mutationsAutosomal dominant polycystic kidney diseaseIntegral membrane proteinsTranscription factor XBP1Unfolded protein responsePost-translational maturationAcid substitution mutationsEndoplasmic reticulum chaperoneCiliary traffickingXBP1 activityChaperone functionIntegral membraneActive XBP1Polycystic kidney diseaseMembrane proteinsPC1 functionsPrimary ciliaProtein responseHypomorphic mutationsTransgenic activationSubstitution mutationsTransgenic expression
2011
A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation
Fedeles SV, Tian X, Gallagher AR, Mitobe M, Nishio S, Lee SH, Cai Y, Geng L, Crews CM, Somlo S. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nature Genetics 2011, 43: 639-647. PMID: 21685914, PMCID: PMC3547075, DOI: 10.1038/ng.860.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBlotting, WesternCell ProliferationCystsFemaleGlucosidasesImmunoenzyme TechniquesImmunoprecipitationIntracellular Signaling Peptides and ProteinsLiver DiseasesMaleMiceMice, Inbred C57BLMice, TransgenicMutationPolycystic Kidney DiseasesReceptors, Cell SurfaceTRPP Cation Channels
2010
Polycystin-2 Activation by Inositol 1,4,5-Trisphosphate-induced Ca2+ Release Requires Its Direct Association with the Inositol 1,4,5-Trisphosphate Receptor in a Signaling Microdomain*
Sammels E, Devogelaere B, Mekahli D, Bultynck G, Missiaen L, Parys JB, Cai Y, Somlo S, De Smedt H. Polycystin-2 Activation by Inositol 1,4,5-Trisphosphate-induced Ca2+ Release Requires Its Direct Association with the Inositol 1,4,5-Trisphosphate Receptor in a Signaling Microdomain*. Journal Of Biological Chemistry 2010, 285: 18794-18805. PMID: 20375013, PMCID: PMC2881802, DOI: 10.1074/jbc.m109.090662.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseasePolycystic kidney diseaseKidney diseaseGlutathione S-transferase pulldown experimentsEndoplasmic reticulumTrisphosphate receptorAgonist-induced intracellularTerminal ligand-binding domainMouse renal epithelial cellsTerminal cytoplasmic tailLigand-binding domainAdenoviral expression systemRenal epithelial cellsSignaling microdomainPathological mutantsPulldown experimentsTrisphosphate-induced Ca2Cytoplasmic tailAcidic clusterPolycystin-1Polycystin-2TRPP2Epithelial cellsExpression system
2004
Mutations in SEC63 cause autosomal dominant polycystic liver disease
Davila S, Furu L, Gharavi AG, Tian X, Onoe T, Qian Q, Li A, Cai Y, Kamath PS, King BF, Azurmendi PJ, Tahvanainen P, Kääriäinen H, Höckerstedt K, Devuyst O, Pirson Y, Martin RS, Lifton RP, Tahvanainen E, Torres VE, Somlo S. Mutations in SEC63 cause autosomal dominant polycystic liver disease. Nature Genetics 2004, 36: 575-577. PMID: 15133510, DOI: 10.1038/ng1357.Peer-Reviewed Original ResearchCalcium Dependence of Polycystin-2 Channel Activity Is Modulated by Phosphorylation at Ser812 *
Cai Y, Anyatonwu G, Okuhara D, Lee KB, Yu Z, Onoe T, Mei CL, Qian Q, Geng L, Wiztgall R, Ehrlich BE, Somlo S. Calcium Dependence of Polycystin-2 Channel Activity Is Modulated by Phosphorylation at Ser812 *. Journal Of Biological Chemistry 2004, 279: 19987-19995. PMID: 14742446, DOI: 10.1074/jbc.m312031200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesBiotinylationCalciumCasein Kinase IICell MembraneDNA, ComplementaryEndoplasmic ReticulumGenes, DominantGlutathione TransferaseGlycosylationMembrane ProteinsMiceMice, Inbred BALB CMicroscopy, FluorescenceMutationPhosphatesPhosphorylationPrecipitin TestsProtein Serine-Threonine KinasesProtein Structure, TertiaryReverse Transcriptase Polymerase Chain ReactionSerineTime FactorsTRPP Cation ChannelsConceptsPolycystin-2Non-phosphorylated formChannel activityCation channelsCultured epithelial cellsActivation/inactivationPolycystic kidney diseaseProtein phosphorylationSubstitution mutantsNon-selective cation channelsConstitutive phosphorylationDivalent cation channelsPolycystin-1Substrate domainEndoplasmic reticulumPhosphorylationSingle-channel studiesVivo analysisControl cellsEpithelial cellsAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseOpen probabilityCellsCK2
2003
Polycystin-1 Distribution Is Modulated by Polycystin-2 Expression in Mammalian Cells*
Grimm DH, Cai Y, Chauvet V, Rajendran V, Zeltner R, Geng L, Avner ED, Sweeney W, Somlo S, Caplan MJ. Polycystin-1 Distribution Is Modulated by Polycystin-2 Expression in Mammalian Cells*. Journal Of Biological Chemistry 2003, 278: 36786-36793. PMID: 12840011, DOI: 10.1074/jbc.m306536200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternCell LineCell MembraneCells, CulturedCOS CellsDNA, ComplementaryEndoplasmic ReticulumGene Expression RegulationMembrane ProteinsMiceMice, TransgenicMicroscopy, FluorescenceModels, BiologicalMutationPrecipitin TestsProtein BindingProtein BiosynthesisProteinsRecombinant Fusion ProteinsRNA, MessengerTransfectionTRPP Cation ChannelsConceptsPolycystin-1Polycystin-2Mammalian cellsLevel of expressionPolycystin-2 expressionEndoplasmic reticulumCell surfaceCOS-7 cellsNull cell lineRelative expression levelsSubcellular localizationFusion proteinGradient of expressionExpression levelsProteinCell linesPolycystinsAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseDivergent patternsExpressionPolycystic kidney diseaseReticulumCellsLocalization
2002
Polycystin-2 is an intracellular calcium release channel
Koulen P, Cai Y, Geng L, Maeda Y, Nishimura S, Witzgall R, Ehrlich BE, Somlo S. Polycystin-2 is an intracellular calcium release channel. Nature Cell Biology 2002, 4: 191-197. PMID: 11854751, DOI: 10.1038/ncb754.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalcium ChannelsCalcium SignalingEndoplasmic ReticulumHumansIn Vitro TechniquesKidneyLLC-PK1 CellsMembrane PotentialsMembrane ProteinsMiceMice, Inbred C57BLMutationMutation, MissensePolycystic Kidney, Autosomal DominantRecombinant ProteinsSequence DeletionSignal TransductionSwineTRPP Cation ChannelsConceptsAutosomal dominant polycystic kidney diseaseIntracellular calcium release channelsPolycystic kidney diseaseCalcium release channelKidney diseaseTransient receptor potential channelsIntracellular calcium releaseDominant polycystic kidney diseaseRelease channelCalcium release signalsPolycystin-2 functionsType 2 autosomal dominant polycystic kidney diseaseCalcium releasePolycystin-2Single-channel studiesEpithelial cellsPotential channelsDiseaseMissense mutationsRelease signalsCarboxy-terminal truncationDisease-causing missense mutations
2000
Cardiac defects and renal failure in mice with targeted mutations in Pkd2
Wu G, Markowitz G, Li L, D'Agati V, Factor S, Geng L, Tibara S, Tuchman J, Cai Y, Hoon Park J, van Adelsberg J, Hou H, Kucherlapati R, Edelmann W, Somlo S. Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nature Genetics 2000, 24: 75-78. PMID: 10615132, DOI: 10.1038/71724.Peer-Reviewed Original ResearchConceptsPolycystin-2True null mutationEmbryonic day 13.5Liver cyst formationSomatic rearrangementsNull mutationNull allelesProtein productsUnstable alleleTargeted mutationsPKD2Cardiac septationCyst formationRenal failureDay 13.5MutationsADPKD phenotypeKidney cystsAllelesLong-term survivalFirst indicationDeleterious effectsCalcium channelsMouse modelClinical manifestations
1999
Aberrant splicing in the PKD2 gene as a cause of polycystic kidney disease.
Reynolds DM, Hayashi T, Cai Y, Veldhuisen B, Watnick TJ, Lens XM, Mochizuki T, Qian F, Maeda Y, Li L, Fossdal R, Coto E, Wu G, Breuning MH, Germino GG, Peters DJ, Somlo S. Aberrant splicing in the PKD2 gene as a cause of polycystic kidney disease. Journal Of The American Society Of Nephrology 1999, 10: 2342-51. PMID: 10541293, DOI: 10.1681/asn.v10112342.Peer-Reviewed Original ResearchConceptsPolycystin-2Mutant polycystin-2Future functional studiesNovel intragenic polymorphismsFrame splice variantsMissense variantsSingle base substitution mutationsPolycystin-2 proteinCryptic splice siteAutosomal dominant polycystic kidney diseaseBase substitution mutationsTransmembrane spansSingle base substitutionPolycystic kidney diseaseSplicing signalsSubunit functionAberrant splicingLymphoblast RNAMutant chromosomesSplice siteSubstitution mutationsPKD2 geneThird mutationBase substitutionsSplice variantsMutations in autosomal dominant polycystic kidney disease 2 gene: Reduced expression of PKD2 protein in lymphoblastoid cells
Aguiari G, Manzati E, Penolazzi L, Micheletti F, Augello G, De Vitali E, Cappelli G, Cai Y, Reynolds D, Somlo S, Piva R, del Senno L. Mutations in autosomal dominant polycystic kidney disease 2 gene: Reduced expression of PKD2 protein in lymphoblastoid cells. American Journal Of Kidney Diseases 1999, 33: 880-885. PMID: 10213643, DOI: 10.1016/s0272-6386(99)70420-8.Peer-Reviewed Original ResearchConceptsPolycystic kidney disease 2 (PKD2) geneMembrane-spanning domainsIntegral membrane proteinsLymphoblastoid cellsFirst extracellular loopAutosomal dominant polycystic kidney diseasePKD2 proteinMembrane proteinsRestriction enzyme analysisCommon genetic diseaseLymphoblastoid cell linesProtein productsMutant allelesExtracellular loopWestern blot analysisPKD2 genePolymerase chain reactionGenetic diseasesNormal proteinAmino acidsMessenger RNA levelsNonsense mutationFrameshift mutationGenesProtein
1998
Somatic Inactivation of Pkd2 Results in Polycystic Kidney Disease
Wu G, D'Agati V, Cai Y, Markowitz G, Park J, Reynolds D, Maeda Y, Le T, Hou H, Kucherlapati R, Edelmann W, Somlo S. Somatic Inactivation of Pkd2 Results in Polycystic Kidney Disease. Cell 1998, 93: 177-188. PMID: 9568711, DOI: 10.1016/s0092-8674(00)81570-6.Peer-Reviewed Original ResearchConceptsCellular recessive mechanismIntragenic homologous recombinationExon 1True null alleleMutant exon 1Somatic inactivationPkd2 resultsRenal cyst formationPKD2 proteinPolycystic kidney diseaseHomologous recombinationNull allelesHuman phenotypesPKD2 expressionUnstable alleleSomatic lossPKD2Autosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseMutationsGermline mutationsRecessive mechanismAllelesInactivationCyst formation
1996
PKD2, a Gene for Polycystic Kidney Disease That Encodes an Integral Membrane Protein
Mochizuki T, Wu G, Hayashi T, Xenophontos S, Veldhuisen B, Saris J, Reynolds D, Cai Y, Gabow P, Pierides A, Kimberling W, Breuning M, Deltas C, Peters D, Somlo S. PKD2, a Gene for Polycystic Kidney Disease That Encodes an Integral Membrane Protein. Science 1996, 272: 1339-1342. PMID: 8650545, DOI: 10.1126/science.272.5266.1339.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsBase SequenceCaenorhabditis elegansCalcium ChannelsChromosome MappingChromosomes, Human, Pair 4Cloning, MolecularConsensus SequenceCrystallography, X-RayFemaleGlycosylationHumansMaleMembrane ProteinsMolecular Sequence DataMutationPedigreePhenotypePolycystic Kidney, Autosomal DominantPolymorphism, Single-Stranded ConformationalProteinsSodium ChannelsTRPP Cation ChannelsConceptsCaenorhabditis elegans homologIntegral membrane proteinsAmino acid similarityPKD2 gene productCalcium-binding domainPKD2 proteinTransmembrane spansPolycystic kidney diseasePositional cloningPotential calcium-binding domainsSecond geneMembrane proteinsGene productsAcid sequenceIntracellular aminoNonsense mutationGenesAutosomal dominant polycystic kidney diseasePKD1Dominant polycystic kidney diseasePKD2 familiesProteinVoltage-activated calcium channelsHomologCalcium channels