2024
CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow
Kim A, Sakin I, Viviano S, Tuncel G, Aguilera S, Goles G, Jeffries L, Ji W, Lakhani S, Kose C, Silan F, Oner S, Kaplan O, Group M, Ergoren M, Mishra-Gorur K, Gunel M, Sag S, Temel S, Deniz E. CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow. Life Science Alliance 2024, 7: e202402708. PMID: 39168639, PMCID: PMC11339347, DOI: 10.26508/lsa.202402708.Peer-Reviewed Original ResearchConceptsDevelopmental disabilitiesIntellectual disabilityPatient-derived fibroblastsMidbrain regionsBrain developmentDefective ciliogenesisCSF circulationDisabilityCSF flowAbnormal CSF flowNervous system developmentMutant tadpolesCiliated tissuesMultiple model systemsVariant functionPronephric ductUnrelated familiesCC2D1AExpression patternsCiliogenesisRenal dysplasiaLeft-right organizerFunctional analysisDisease mechanismsBrainPathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics
DeSpenza T, Singh A, Allington G, Zhao S, Lee J, Kiziltug E, Prina M, Desmet N, Dang H, Fields J, Nelson-Williams C, Zhang J, Mekbib K, Dennis E, Mehta N, Duy P, Shimelis H, Walsh L, Marlier A, Deniz E, Lake E, Constable R, Hoffman E, Lifton R, Gulledge A, Fiering S, Moreno-De-Luca A, Haider S, Alper S, Jin S, Kahle K, Luikart B. Pathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2314702121. PMID: 38916997, PMCID: PMC11228466, DOI: 10.1073/pnas.2314702121.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusCerebral ventriculomegalyPathogenic variantsPrefrontal pyramidal neuronsGenetic subsets of patientsDevelopment of ventriculomegalyRadial gliaSubsets of patientsHigh-frequency firingNeuronal connectivityHeterozygous germline variantsAutism spectrum disorderVentricular-subventricular zoneMicrotubule dynamicsImpaired spermatogenesisCSF shuntingExcitatory driveMicrotubule-severing ATPasePyramidal neuronsDisrupt neuronal connectivityGermline variantsVentriculomegalyCSF homeostasisDisrupt microtubule dynamicsPlanar cell polarity
2023
CFAP45, a heterotaxy and congenital heart disease gene, affects cilia stability
Deniz E, Pasha M, Guerra M, Viviano S, Ji W, Konstantino M, Jeffries L, Lakhani S, Medne L, Skraban C, Krantz I, Khokha M. CFAP45, a heterotaxy and congenital heart disease gene, affects cilia stability. Developmental Biology 2023, 499: 75-88. PMID: 37172641, PMCID: PMC10373286, DOI: 10.1016/j.ydbio.2023.04.006.Peer-Reviewed Original ResearchConceptsLeft-right organizerCilia stabilityLeft-right patterningCongenital heart disease genesApical surfaceCell apical surfaceLive confocal imagingLeftward fluid flowHeart disease genesRecessive missense mutationLethal birth defectMotile monociliaProtein familyEarly embryogenesisMulticiliated cellsCiliary axonemeDisease genesFrog embryosGenetic underpinningsWhole-exome sequencingMissense mutationsConfocal imagingEmbryosCiliaCongenital heart diseasePleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease
Mishra-Gorur K, Barak T, Kaulen L, Henegariu O, Jin S, Aguilera S, Yalbir E, Goles G, Nishimura S, Miyagishima D, Djenoune L, Altinok S, K. D, Viviano S, Prendergast A, Zerillo C, Ozcan K, Baran B, Sencar L, Goc N, Yarman Y, Ercan-Sencicek A, Bilguvar K, Lifton R, Moliterno J, Louvi A, Yuan S, Deniz E, Brueckner M, Gunel M. Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2214997120. PMID: 37043537, PMCID: PMC10120005, DOI: 10.1073/pnas.2214997120.Peer-Reviewed Original ResearchConceptsWild-type proteinInherited mutationsCardiac outflow tractDevelopmental heart defectsProtein functionLack ciliaPleiotropic rolesMechanistic convergenceNeural crestCiliary defectsSomatic variantsForebrain meningesCommon originDominant mannerMutationsTRAF7ZebrafishMutantsDisparate pathologiesHeterodimerizationKnockdownGeneticsProteinCiliaCongenital heart
2022
Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus
Duy PQ, Weise SC, Marini C, Li XJ, Liang D, Dahl PJ, Ma S, Spajic A, Dong W, Juusola J, Kiziltug E, Kundishora AJ, Koundal S, Pedram MZ, Torres-Fernández LA, Händler K, De Domenico E, Becker M, Ulas T, Juranek SA, Cuevas E, Hao LT, Jux B, Sousa AMM, Liu F, Kim SK, Li M, Yang Y, Takeo Y, Duque A, Nelson-Williams C, Ha Y, Selvaganesan K, Robert SM, Singh AK, Allington G, Furey CG, Timberlake AT, Reeves BC, Smith H, Dunbar A, DeSpenza T, Goto J, Marlier A, Moreno-De-Luca A, Yu X, Butler WE, Carter BS, Lake EMR, Constable RT, Rakic P, Lin H, Deniz E, Benveniste H, Malvankar NS, Estrada-Veras JI, Walsh CA, Alper SL, Schultze JL, Paeschke K, Doetzlhofer A, Wulczyn FG, Jin SC, Lifton RP, Sestan N, Kolanus W, Kahle KT. Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus. Nature Neuroscience 2022, 25: 458-473. PMID: 35379995, PMCID: PMC9664907, DOI: 10.1038/s41593-022-01043-3.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusCerebral ventricular dilatationPrimary defectNeuroepithelial cell differentiationRisk genesCerebrospinal fluid homeostasisWhole-exome sequencingNeuroepithelial stem cellsCortical hypoplasiaReduced neurogenesisVentricular dilatationVentricular enlargementCH mutationsPrenatal hydrocephalusDisease heterogeneityBrain surgeryCSF circulationHydrocephalusGenetic subtypesFluid homeostasisNeuroepithelial cellsNovo mutationsBrain transcriptomicsStem cellsCell differentiation
2021
Xenopus Tadpole Craniocardiac Imaging Using Optical Coherence Tomography.
Deniz E, Mis EK, Lane M, Khokha MK. Xenopus Tadpole Craniocardiac Imaging Using Optical Coherence Tomography. Cold Spring Harbor Protocols 2021, 2022: pdb.prot105676. PMID: 34031211, DOI: 10.1101/pdb.prot105676.Peer-Reviewed Original Research
2020
In Xenopus ependymal cilia drive embryonic CSF circulation and brain development independently of cardiac pulsatile forces
Dur AH, Tang T, Viviano S, Sekuri A, Willsey HR, Tagare HD, Kahle KT, Deniz E. In Xenopus ependymal cilia drive embryonic CSF circulation and brain development independently of cardiac pulsatile forces. Fluids And Barriers Of The CNS 2020, 17: 72. PMID: 33308296, PMCID: PMC7731788, DOI: 10.1186/s12987-020-00234-z.Peer-Reviewed Original ResearchConceptsCSF circulationOptical coherence tomographyCSF flowVentricular systemEpendymal ciliaCoherence tomographyBrain developmentCross-sectional imaging modalitiesBrain ventricular systemEarly time pointsVentricular morphologyCerebral ventricleRespiratory forceConclusionsOur dataCerebrospinal fluidChoroid plexusVentricular spaceCardiac forceEmbryonic brainPulsatile forcesDeadly diseaseTime pointsImaging modalitiesOCT imagingPathological expansionPaired Box 9 (PAX9), the RNA polymerase II transcription factor, regulates human ribosome biogenesis and craniofacial development
Farley-Barnes KI, Deniz E, Overton MM, Khokha MK, Baserga SJ. Paired Box 9 (PAX9), the RNA polymerase II transcription factor, regulates human ribosome biogenesis and craniofacial development. PLOS Genetics 2020, 16: e1008967. PMID: 32813698, PMCID: PMC7437866, DOI: 10.1371/journal.pgen.1008967.Peer-Reviewed Original ResearchConceptsRNA polymerase II transcription factorsCraniofacial developmentTranscription factorsRibosome biogenesis factorsHuman ribosome biogenesisNeural crest developmentBox 9Tissue-specific mannerRibosome biogenesisRibosome productionHuman ribosomopathiesExpression of proteinsPax9 functionBiogenesis factorsXenopus tropicalisCrest developmentSmall subunitEmbryonic developmentCellular machinesUnexpected layerLevels of proteinRibosomopathiesHuman cellsProtein synthesisRibosomesDLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes
Marquez J, Mann N, Arana K, Deniz E, Ji W, Konstantino M, Mis EK, Deshpande C, Jeffries L, McGlynn J, Hugo H, Widmeier E, Konrad M, Tasic V, Morotti R, Baptista J, Ellard S, Lakhani SA, Hildebrandt F, Khokha MK. DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes. Journal Of Medical Genetics 2020, 58: 453-464. PMID: 32631816, PMCID: PMC7785698, DOI: 10.1136/jmedgenet-2019-106805.Peer-Reviewed Original ResearchConceptsLoss of ciliaPatient tissuesPatient variantsCongenital heart diseaseMultiple organ systemsMultiple congenital anomaliesDLG5 variantsVariety of pathologiesNephrotic syndromeHeart diseaseCongenital anomaliesRespiratory tractKidney tissueOrgan systemsCystic kidneysPatient phenotypesKidneyDiseaseLimb abnormalitiesUnrelated familiesRescue experimentsCraniofacial malformationsCilia dysfunctionTissue-specific manifestationsTissue
2019
Visualizing flow in an intact CSF network using optical coherence tomography: implications for human congenital hydrocephalus
Date P, Ackermann P, Furey C, Fink IB, Jonas S, Khokha MK, Kahle KT, Deniz E. Visualizing flow in an intact CSF network using optical coherence tomography: implications for human congenital hydrocephalus. Scientific Reports 2019, 9: 6196. PMID: 30996265, PMCID: PMC6470164, DOI: 10.1038/s41598-019-42549-4.Peer-Reviewed Original ResearchConceptsCSF flow dynamicsCongenital hydrocephalusOptical coherence tomographyCH pathophysiologyVentricular systemCoherence tomographyBrain developmentCurrent treatment modalitiesHuman congenital hydrocephalusCerebrospinal fluid flowAqueductal stenosisCerebral ventricleNeurosurgical indicationsTreatment modalitiesSurgery techniquesBrain ventriclesEpendymal ciliaCSF flowCiliary dysfunctionHuman L1CAMHydrocephalus pathogenesisVivo investigationsHydrocephalusPathophysiologyVentricle
2018
CRISPR/Cas9 F0 Screening of Congenital Heart Disease Genes in Xenopus tropicalis
Deniz E, Mis EK, Lane M, Khokha MK. CRISPR/Cas9 F0 Screening of Congenital Heart Disease Genes in Xenopus tropicalis. Methods In Molecular Biology 2018, 1865: 163-174. PMID: 30151766, DOI: 10.1007/978-1-4939-8784-9_12.Peer-Reviewed Original ResearchConceptsCardiac developmentCRISPR/Candidate genesHigh-density SNP arrayCRISPR/Cas9 systemGenome editing technologyCongenital heart disease genesNew genomic technologiesHeart disease genesCopy number variationsRapid functional assayXenopus tropicalisCas9 systemGenetic basisDevelopmental systemsEditing technologyGenomic technologiesSequence variationDisease genesDifferent genesGenetic analysisSNP arrayDevelopmental mechanismsMolecular mechanismsWhole-exome sequencing
2017
Analysis of Craniocardiac Malformations in Xenopus using Optical Coherence Tomography
Deniz E, Jonas S, Hooper M, N. Griffin J, Choma MA, Khokha MK. Analysis of Craniocardiac Malformations in Xenopus using Optical Coherence Tomography. Scientific Reports 2017, 7: 42506. PMID: 28195132, PMCID: PMC5307353, DOI: 10.1038/srep42506.Peer-Reviewed Original ResearchConceptsCandidate genesFrog Xenopus tropicalisHuman congenital heart diseaseMost candidate genesNumerous candidate genesHuman genomic studiesXenopus tropicalisGenomic studiesXenopus heartGenetic mechanismsSequence variationFunctional analysisHuman phenotypesMolecular mechanismsHuman diseasesGenesCraniofacial defectsDisease mechanismsCraniofacial malformationsCritical first stepBirth defectsXenopusEfficient animal modelMechanismPhenocopies