Featured Publications
A Founder Mutation as a Cause of Cerebral Cavernous Malformation in Hispanic Americans
Günel M, Awad I, Finberg K, Anson J, Steinberg G, Batjer H, Kopitnik T, Morrison L, Giannotta S, Nelson-Williams C, Lifton R. A Founder Mutation as a Cause of Cerebral Cavernous Malformation in Hispanic Americans. New England Journal Of Medicine 1996, 334: 946-951. PMID: 8596595, DOI: 10.1056/nejm199604113341503.Peer-Reviewed Original ResearchConceptsCavernous malformationsCerebral cavernous malformationsSporadic casesFamilial diseaseSame mutationSporadic cavernous malformationsDevelopment of symptomsHispanic AmericansCerebral hemorrhageVascular diseaseAsymptomatic carriersHigh prevalenceClinical casesMalformationsDiseaseFounder mutationPatientsAge dependenceAffected membersKindredsMarkersMexican descentEthnic groupsMutationsSame alleleCombined HMG-COA reductase and prenylation inhibition in treatment of CCM
Nishimura S, Mishra-Gorur K, Park J, Surovtseva YV, Sebti SM, Levchenko A, Louvi A, Gunel M. Combined HMG-COA reductase and prenylation inhibition in treatment of CCM. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 5503-5508. PMID: 28500274, PMCID: PMC5448170, DOI: 10.1073/pnas.1702942114.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAstrocytesDiphosphonatesDrosophilaDrug Evaluation, PreclinicalDrug Therapy, CombinationEndothelial CellsFatty Acids, MonounsaturatedFemaleFluvastatinHemangioma, Cavernous, Central Nervous SystemHigh-Throughput Screening AssaysHydroxymethylglutaryl-CoA Reductase InhibitorsImidazolesIndolesMaleMAP Kinase Signaling SystemMicePregnancyProtein PrenylationZoledronic AcidConceptsCerebral cavernous malformationsTreatment of CCMsCommon vascular anomaliesPotential pharmacological treatment optionsFocal neurological deficitsPharmacological treatment optionsCCM diseaseAcute mouse modelCentral nervous systemNeurological deficitsHemorrhagic strokePharmacological therapyLesion burdenVascular deficitsSymptomatic lesionsCombination therapyTreatment optionsVascular anomaliesGlial cellsCavernous malformationsMouse modelPrimary astrocytesNervous systemDrug AdministrationSustained inhibition
2014
Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations
Shenkar R, Shi C, Rebeiz T, Stockton RA, McDonald DA, Mikati AG, Zhang L, Austin C, Akers AL, Gallione CJ, Rorrer A, Gunel M, Min W, Marcondes de Souza J, Lee C, Marchuk DA, Awad IA. Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. Genetics In Medicine 2014, 17: 188-196. PMID: 25122144, PMCID: PMC4329119, DOI: 10.1038/gim.2014.97.Peer-Reviewed Original ResearchMeSH Keywords1-(5-Isoquinolinesulfonyl)-2-MethylpiperazineAdolescentAdultAnimalsApoptosis Regulatory ProteinsCarrier ProteinsCells, CulturedCentral Nervous System NeoplasmsChildChild, PreschoolDisease Models, AnimalHemangioma, Cavernous, Central Nervous SystemHuman Umbilical Vein Endothelial CellsHumansInfantIntracellular Signaling Peptides and ProteinsKeratin-1Membrane ProteinsMiceMiddle AgedMutationProspective StudiesProto-Oncogene ProteinsRho-Associated KinasesStress FibersYoung AdultConceptsCerebral cavernous malformation diseaseRho-kinase activityLesion burdenExceptional aggressivenessCerebral cavernous malformation lesionsSporadic cerebral cavernous malformationBrain vascular permeabilityPreclinical therapeutic testingDesign of trialsPotential therapeutic targetCerebral cavernous malformationsClinical manifestationsBrain permeabilityEndothelial stress fibersSkin lesionsVascular permeabilityCavernous malformationsTherapeutic targetTherapeutic testingFrequent hemorrhagesKinase activityClinical phenotypeClinical counselingHeterozygous miceEndothelial cellsCcm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration
Louvi A, Nishimura S, Günel M. Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration. Development 2014, 141: 1404-1415. PMID: 24595293, PMCID: PMC3943187, DOI: 10.1242/dev.093526.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosis Regulatory ProteinsCell MovementCell ProliferationCyclin-Dependent Kinase 5FemaleHemangioma, Cavernous, Central Nervous SystemIntracellular Signaling Peptides and ProteinsMiceMice, KnockoutMice, TransgenicNeocortexNeural Stem CellsNeurogliaPregnancyRho GTP-Binding ProteinsRhoA GTP-Binding ProteinSignal TransductionConceptsCerebral cavernous malformation 3Neuronal migrationCerebral cavernous malformationsRadial glia progenitorsCell non-autonomous functionCerebrovascular disordersPyramidal neuronsCortical plateLaminar positioningSubventricular zoneCortical developmentCavernous malformationsRadial gliaLoss of functionNascent neuronsNeuronal morphologySevere malformationsGlia progenitorsNeural progenitorsNeuronsNon-autonomous functionsMalformationsRhoA pathwayPossible interactionsGlia
2011
CCM2 expression during prenatal development and adult human neocortex
Tanriover G, Sozen B, Gunel M, Demir N. CCM2 expression during prenatal development and adult human neocortex. International Journal Of Developmental Neuroscience 2011, 29: 509-514. PMID: 21569831, DOI: 10.1016/j.ijdevneu.2011.04.006.Peer-Reviewed Original ResearchConceptsAdult human neocortexCerebral cavernous malformationsHuman neocortexNeuroglial precursor cellsPrenatal developmentMeans of immunohistochemistryCentral nervous systemWestern blot analysisHuman brain developmentVascular malformationsAdult neocortexGlial cellsCavernous malformationsCCM lesionsVascular endotheliumNervous systemVascular channelsBlood vessel formationArterial endotheliumBrain developmentNeocortexExpression patternsEndotheliumPrecursor cellsCCM lociLoss of cerebral cavernous malformation 3 (Ccm3) in neuroglia leads to CCM and vascular pathology
Louvi A, Chen L, Two AM, Zhang H, Min W, Günel M. Loss of cerebral cavernous malformation 3 (Ccm3) in neuroglia leads to CCM and vascular pathology. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 3737-3742. PMID: 21321212, PMCID: PMC3048113, DOI: 10.1073/pnas.1012617108.Peer-Reviewed Original ResearchConceptsNeural cellsCerebral cavernous malformationsCell-nonautonomous mechanismsPathogenesis of CCMsRho GTPase signalingCell-autonomous mechanismsCell-autonomous roleCerebral cavernous malformation 3Cell death 10Central nervous systemConditional mouse mutantsNonautonomous functionsCytoskeletal remodelingRNA sequencingCCM3/Mouse mutantsNeurovascular unitNonautonomous mechanismsProper developmentVascular lesionsGene 1Function mutationsNervous systemAutonomous mechanismsLate functions
2010
Stabilization of VEGFR2 Signaling by Cerebral Cavernous Malformation 3 Is Critical for Vascular Development
He Y, Zhang H, Yu L, Gunel M, Boggon TJ, Chen H, Min W. Stabilization of VEGFR2 Signaling by Cerebral Cavernous Malformation 3 Is Critical for Vascular Development. Science Signaling 2010, 3: ra26. PMID: 20371769, PMCID: PMC3052863, DOI: 10.1126/scisignal.2000722.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCardiovascular SystemEndothelial CellsFluorescent Antibody Technique, IndirectGene DeletionGene Expression ProfilingGene Knockdown TechniquesHematopoiesisHumansImmunoblottingImmunohistochemistryImmunoprecipitationMiceReverse Transcriptase Polymerase Chain ReactionSignal TransductionVascular Endothelial Growth Factor Receptor-2ConceptsCarboxyl-terminal domainVascular endothelial growth factor receptor 2Vascular developmentHuman vascular malformationsCerebral cavernous malformation 3Early embryonic stagesCerebral cavernous malformationsEndothelial cell-specific deletionApoptotic stimuliCell-specific deletionVivo functionEmbryonic angiogenesisEndothelial growth factor receptor 2Unknown functionVEGF stimulationVEGFR2 signalingEmbryonic stagesMessenger RNASmooth muscle cellsGrowth factor receptor 2DeletionCCM3 genesFactor receptor 2Muscle cellsGenes
2009
CCM2 and CCM3 proteins contribute to vasculogenesis and angiogenesis in human placenta.
Tanriover G, Seval Y, Sati L, Gunel M, Demir N. CCM2 and CCM3 proteins contribute to vasculogenesis and angiogenesis in human placenta. Histology And Histopathology 2009, 24: 1287-94. PMID: 19688696, DOI: 10.14670/hh-24.1287.Peer-Reviewed Original ResearchMeSH KeywordsApoptosis Regulatory ProteinsCarrier ProteinsCase-Control StudiesCentral Nervous System NeoplasmsFemaleHemangioma, Cavernous, Central Nervous SystemHumansImmunohistochemistryMembrane ProteinsNeovascularization, PathologicPlacentaPregnancyPregnancy Trimester, FirstPregnancy Trimester, ThirdProto-Oncogene ProteinsConceptsCerebral cavernous malformationsVascular endotheliumBlood vessel formationHuman placentaMature intermediate villiVascular malformationsStem villiTerm placentaVessel formationIntermediate villiNormal brain parenchymaMeans of immunohistochemistryCentral nervous systemEndothelium-lined vascular channelsWestern blot analysisEarly pregnancyBrain parenchymaModerate immunostainingCavernous malformationsNervous systemVascular channelsPlacental developmentPlacentaEndotheliumLess expression
2007
A novel syndrome of cerebral cavernous malformation and Greig cephalopolysyndactyly. Laboratory investigation.
Bilguvar K, Bydon M, Bayrakli F, Ercan-Sencicek AG, Bayri Y, Mason C, DiLuna ML, Seashore M, Bronen R, Lifton RP, State M, Gunel M. A novel syndrome of cerebral cavernous malformation and Greig cephalopolysyndactyly. Laboratory investigation. Journal Of Neurosurgery 2007, 107: 495-9. PMID: 18154020, DOI: 10.3171/ped-07/12/495.Peer-Reviewed Original ResearchMeSH KeywordsAbnormalities, MultipleCarrier ProteinsChild, PreschoolChromosome DeletionChromosomes, Human, Pair 7Craniofacial AbnormalitiesDNAFemaleGene DosageHemangioma, Cavernous, Central Nervous SystemHeterozygoteHumansKruppel-Like Transcription FactorsNerve Tissue ProteinsOligonucleotide Array Sequence AnalysisReverse Transcriptase Polymerase Chain ReactionSyndromeZinc Finger Protein Gli3ConceptsGreig cephalopolysyndactyly syndromeCerebral cavernous malformationsDeleterious genetic variantsComparative genome hybridization analysisChromosome 7pArray-based CGHGene GLI3Distinct genesMultiple genesGenetic analysisGenomic DNANovel syndromeGenomic lesionsChromosome 7Contiguous gene syndromeQuantitative real-time polymerase chain reactionQuantitative RT-PCRGli3Hybridization analysis
2005
CCM2 Expression Parallels That of CCM1
Seker A, Pricola KL, Guclu B, Ozturk AK, Louvi A, Gunel M. CCM2 Expression Parallels That of CCM1. Stroke 2005, 37: 518-523. PMID: 16373645, DOI: 10.1161/01.str.0000198835.49387.25.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternBrainCarrier ProteinsCells, CulturedCentral Nervous SystemCerebral CortexChlorocebus aethiopsCOS CellsEndothelium, VascularHumansImmunohistochemistryIn Situ HybridizationKRIT1 ProteinMiceMicrotubule-Associated ProteinsMuscle, SmoothMutationNeuronsPhenotypeProto-Oncogene ProteinsRNA, MessengerSignal TransductionTime FactorsTwo-Hybrid System TechniquesUmbilical VeinsConceptsCerebral cavernous malformationsProtein expressionExtracerebral tissuesFamilial cerebral cavernous malformationsArterial vascular endotheliumPostnatal mouse brainSmooth muscle cellsVascular wall elementsWestern blot analysisExpression patternsPyramidal neuronsVenous circulationCerebral tissueNeurovascular diseasesCavernous malformationsImmunohistochemical analysisVascular endotheliumMouse brainMRNA expressionMuscle cellsFoot processesEpithelial cellsExpression parallelsDisease phenotypeSpatial expression patternsCerebral Venous Malformations Have Distinct Genetic Origin From Cerebral Cavernous Malformations
Guclu B, Ozturk AK, Pricola KL, Seker A, Ozek M, Gunel M. Cerebral Venous Malformations Have Distinct Genetic Origin From Cerebral Cavernous Malformations. Stroke 2005, 36: 2479-2480. PMID: 16239636, DOI: 10.1161/01.str.0000183616.99139.d3.Peer-Reviewed Original ResearchMeSH KeywordsApoptosis Regulatory ProteinsBlood VesselsCarrier ProteinsChildDNA Mutational AnalysisExonsFamily HealthFemaleFrameshift MutationGene Expression RegulationHumansIntracranial Arteriovenous MalformationsKRIT1 ProteinMaleMembrane ProteinsMicrotubule-Associated ProteinsModels, GeneticMutationPedigreeProto-Oncogene ProteinsConceptsMutational analysisCerebral cavernous malformationsDistinct genetic originsCCM genesCerebral venous malformationSuch mutationsCausative genesUnique familyFrameshift mutationGenesGenetic originCCM1 geneCommon originMutationsFamilyVenous malformationsPathogenetic mechanismsCavernous malformationsMembersDistinct biologyPDCD10BiologyExon 19KRIT1Different pathogenetic mechanisms
2004
Krev1 interaction trapped-1/cerebral cavernous malformation-1 protein expression during early angiogenesis.
Guzeloglu-Kayisli O, Kayisli UA, Amankulor NM, Voorhees JR, Gokce O, DiLuna ML, Laurans MS, Luleci G, Gunel M. Krev1 interaction trapped-1/cerebral cavernous malformation-1 protein expression during early angiogenesis. Journal Of Neurosurgery 2004, 100: 481-7. PMID: 15287459, DOI: 10.3171/ped.2004.100.5.0481.Peer-Reviewed Original ResearchKRIT1/Cerebral Cavernous Malformation 1 Protein Localizes to Vascular Endothelium, Astrocytes, and Pyramidal Cells of the Adult Human Cerebral Cortex
Guzeloglu-Kayisli O, Amankulor NM, Voorhees J, Luleci G, Lifton RP, Gunel M. KRIT1/Cerebral Cavernous Malformation 1 Protein Localizes to Vascular Endothelium, Astrocytes, and Pyramidal Cells of the Adult Human Cerebral Cortex. Neurosurgery 2004, 54: 943-949. PMID: 15046662, DOI: 10.1227/01.neu.0000114512.59624.a5.Peer-Reviewed Original ResearchMeSH KeywordsAdultAstrocytesBlotting, WesternBrain NeoplasmsCerebral CortexChromosome AberrationsEndothelium, VascularGene Expression Regulation, NeoplasticGenes, DominantHemangioma, CavernousHemangioma, Cavernous, Central Nervous SystemHumansImmunoenzyme TechniquesKRIT1 ProteinMicrotubule-Associated ProteinsProto-Oncogene ProteinsPyramidal CellsConceptsCerebral cavernous malformationsCerebral cortexCavernous malformationsVascular endotheliumCentral nervous system vasculatureAdult human cerebral cortexEndothelial cellsCerebral cavernous malformation lesionsBlood-brain barrierAstrocytic foot processesFamilial cerebral cavernous malformationsHuman cerebral cortexCentral nervous systemAutosomal dominant disorderCerebral angiogenesisPyramidal neuronsPyramidal cellsBlood-organ barriersNervous systemWhite pulpRed pulpIntense stainingWestern blottingFoot processesCardiac myocytes
2002
KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein
Gunel M, Laurans MS, Shin D, DiLuna ML, Voorhees J, Choate K, Nelson-Williams C, Lifton RP. KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein. Proceedings Of The National Academy Of Sciences Of The United States Of America 2002, 99: 10677-10682. PMID: 12140362, PMCID: PMC125011, DOI: 10.1073/pnas.122354499.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsAortaCattleCells, CulturedCentral Nervous System Vascular MalformationsChlorocebus aethiopsCOS CellsEndothelium, VascularGene ExpressionMicrotubule-Associated ProteinsMicrotubulesMitosisMolecular Sequence DataMutagenesisPrecipitin TestsProto-Oncogene ProteinsRadiographyTubulinConceptsCerebral cavernous malformationsCavernous malformationsCerebral cavernous malformation lesionsMicrotubule-associated proteinsProtein-1 alphaAutosomal dominant diseaseEndothelial tube formationCerebral hemorrhageCerebral capillariesEndothelial cellsDominant diseaseMalformationsTube formationPlus endsSite of cytokinesisSpindle pole bodyEvidence of interactionGene 1Possible roleCell-matrix interactionsKRIT1Late phaseEnds of microtubulesEndothelial cell shapePole body
1996
Genetic Heterogeneity of Inherited Cerebral Cavernous Malformation
Günel M, Awad I, Finberg K, Steinberg G, Craig H, Cepeda O, Nelson-Williams C, Lifton R. Genetic Heterogeneity of Inherited Cerebral Cavernous Malformation. Neurosurgery 1996, 38: 1265-1271. DOI: 10.1227/00006123-199606000-00059.Peer-Reviewed Original ResearchConceptsGenetic analysisCauses of CCMsCerebral cavernous malformationsHuman chromosome 7Second geneIndependent inheritanceMutant geneChromosome 7Genetic markersGenesLong armGenetic heterogeneityMutationsCavernous malformationsInheritanceFamilyAutosomal dominant transmissionClinical featuresGenetic testingDominant transmissionKindredsMarkersNon-Hispanic familiesMalformationsDisordersGenetic heterogeneity of inherited cerebral cavernous malformation.
Günel M, Awad I, Finberg K, Steinberg G, Craig H, Cepeda O, Carol N, Lifton R. Genetic heterogeneity of inherited cerebral cavernous malformation. Neurosurgery 1996, 38: 1265-71. PMID: 8727164, DOI: 10.1097/00006123-199606000-00059.Peer-Reviewed Original ResearchConceptsGenetic analysisCauses of CCMsCerebral cavernous malformationsHuman chromosome 7Second geneIndependent inheritanceMutant geneChromosome 7Genetic markersGenesLong armGenetic heterogeneityMutationsCavernous malformationsInheritanceFamilyAutosomal dominant transmissionClinical featuresGenetic testingDominant transmissionKindredsMarkersNon-Hispanic familiesMalformationsDisorders
1995
Mapping a gene causing cerebral cavernous malformation to 7q11.2-q21.
Günel M, Awad IA, Anson J, Lifton RP. Mapping a gene causing cerebral cavernous malformation to 7q11.2-q21. Proceedings Of The National Academy Of Sciences Of The United States Of America 1995, 92: 6620-6624. PMID: 7604043, PMCID: PMC41570, DOI: 10.1073/pnas.92.14.6620.Peer-Reviewed Original ResearchMeSH KeywordsBrainChromosome MappingChromosomes, Human, Pair 7DNAFemaleGenes, DominantGenetic LinkageGenetic MarkersGenome, HumanHemangioma, CavernousHumansMagnetic Resonance ImagingMaleMolecular Sequence DataPedigreePolymerase Chain ReactionPolymorphism, GeneticRecombination, GeneticRepetitive Sequences, Nucleic AcidConceptsCerebral cavernous malformationsCavernous malformationsAutosomal dominant inheritanceHemorrhagic strokeClinical presentationUnknown cause