2025
Phenotypic complexities of rare heterozygous neurexin-1 deletions
Fernando M, Fan Y, Zhang Y, Tokolyi A, Murphy A, Kammourh S, Deans P, Ghorbani S, Onatzevitch R, Pero A, Padilla C, Williams S, Flaherty E, Prytkova I, Cao L, Knowles D, Fang G, Slesinger P, Brennand K. Phenotypic complexities of rare heterozygous neurexin-1 deletions. Nature 2025, 642: 710-720. PMID: 40205044, DOI: 10.1038/s41586-025-08864-9.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAnimalsCalcium-Binding ProteinsCell Adhesion Molecules, NeuronalDNA Copy Number VariationsFemaleGABAergic NeuronsGene DeletionHeterozygoteHumansInduced Pluripotent Stem CellsLoss of Function MutationMaleMiceNeural Cell Adhesion MoleculesPhenotypeSequence DeletionSynapsesConceptsLoss-of-functionGain-of-functionGain-of-function mechanismCopy number variantsSynaptic activityCell type-specific effectsCell adhesion proteinsPrecision medicineIncreased wild-typeSplicing resultsAlternative splicingIsoform repertoireNRXN1 deletionsAberrant splicingHuman induced pluripotent stem cellsPatient-specific mutationsIncreased synaptic activityDecreased synaptic activityMutant isoformsNRXN1Associated with riskPluripotent stem cellsHeterozygous deletionWild-typeDeletionA personalised and comprehensive approach is required to suppress or replenish SNCA for Parkinson’s disease
Li D, Yau W, Chen S, Wilton S, Mastaglia F. A personalised and comprehensive approach is required to suppress or replenish SNCA for Parkinson’s disease. Npj Parkinson's Disease 2025, 11: 42. PMID: 40038287, PMCID: PMC11880543, DOI: 10.1038/s41531-025-00887-3.Peer-Reviewed Original ResearchModeling SMAD2 Mutations in Induced Pluripotent Stem Cells Provides Insights Into Cardiovascular Disease Pathogenesis
Ward T, Morton S, Venturini G, Tai W, Jang M, Gorham J, Delaughter D, Wasson L, Khazal Z, Homsy J, Gelb B, Chung W, Bruneau B, Brueckner M, Tristani-Firouzi M, DePalma S, Seidman C, Seidman J. Modeling SMAD2 Mutations in Induced Pluripotent Stem Cells Provides Insights Into Cardiovascular Disease Pathogenesis. Journal Of The American Heart Association 2025, 14: e036860. PMID: 40028843, PMCID: PMC12184555, DOI: 10.1161/jaha.124.036860.Peer-Reviewed Original ResearchConceptsLoss-of-functionCongenital heart diseaseChromatin accessibilityMissense variantsCHD probandsPluripotent stem cellsHomozygous loss-of-functionCHD-associated genesHeterozygous loss-of-functionTranscription factor bindingMutant induced pluripotent stem cellsChromatin immunoprecipitation dataChromatin peaksStem cellsChromatin interactionsInduced pluripotent stem cellsFactor bindingTranscription factor NanogExome sequencingImmunoprecipitation dataTranscription factorsRNA sequencingChromatinMissenseMolecular consequencesInvestigating the Contribution of Coding Variants in Alcohol Use Disorder Using Whole-Exome Sequencing Across Ancestries
Wang L, Kranzler H, Gelernter J, Zhou H. Investigating the Contribution of Coding Variants in Alcohol Use Disorder Using Whole-Exome Sequencing Across Ancestries. Biological Psychiatry 2025, 98: 46-55. PMID: 39892688, PMCID: PMC12167164, DOI: 10.1016/j.biopsych.2025.01.020.Peer-Reviewed Original ResearchContribution of coding variantsGene-based collapsing testAlcohol use disorderAnalyzed whole-exome sequencing dataEuropean ancestryContribution of rare coding variantsRare loss-of-functionWhole-exome sequencing dataWhole-exome sequencing studiesRare Coding VariantsAfrican ancestryWhole-exome sequencingLoss-of-functionGenetic architectureSequence dataAllelic heterogeneityMissense variantsGenetic variantsAllele frequenciesRare variantsYale-PennStudy of alcohol use disorderUK BiobankUK Biobank cohortVariants
2024
Rare genetic variation in fibronectin 1 (FN1) protects against APOE ɛ4 in Alzheimer’s Disease
Bhattarai P, Gunasekaran T, Uzrek B, Reyes‐Dumeyer D, Jülich D, Lee A, Yilmaz E, Tayran H, Lantigua R, Medrano M, Mejia D, Recio P, Flaherty D, Dalgard C, Nuriel T, Ertekin‐Taner N, Dickson D, Teich A, Holley S, Mayeux R, Kizil C, Vardarajan B. Rare genetic variation in fibronectin 1 (FN1) protects against APOE ɛ4 in Alzheimer’s Disease. Alzheimer's & Dementia 2024, 20: e089111. PMCID: PMC11710415, DOI: 10.1002/alz.089111.Peer-Reviewed Original ResearchWhole-genome sequencingLoss-of-functionIn vivo functional studiesFibronectin 1Genetic variationAlzheimer's diseaseFunctional studiesWhole-genome sequence analysisTarget genesRare genetic variationLoss-of-function mutationsPotential gene variantsZebrafish modelGenome sequenceProtective variantsAPOE variantsGenetic variantsECM proteinsZebrafish AD modelBioinformatics analysisAD pathologyPotential therapeutic interventional targetsPathway analysisPostmortem human brain tissueRare variantsRare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease
Bhattarai P, Gunasekaran T, Belloy M, Reyes-Dumeyer D, Jülich D, Tayran H, Yilmaz E, Flaherty D, Turgutalp B, Sukumar G, Alba C, McGrath E, Hupalo D, Bacikova D, Le Guen Y, Lantigua R, Medrano M, Rivera D, Recio P, Nuriel T, Ertekin-Taner N, Teich A, Dickson D, Holley S, Greicius M, Dalgard C, Zody M, Mayeux R, Kizil C, Vardarajan B. Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease. Acta Neuropathologica 2024, 147: 70. PMID: 38598053, PMCID: PMC11006751, DOI: 10.1007/s00401-024-02721-1.Peer-Reviewed Original ResearchConceptsLoss-of-functionWhole-genome sequencingFibronectin 1Genetic variationAlzheimer's diseaseAD riskRare Coding VariantsLoss-of-function variantsRare genetic variationGene Ontology termsFamily based studyIn vivo functional studiesAD-related pathologyAlpha 2 chainOntology termsPresence of cellular mechanismsProtective variantsECM proteinsAD pathologyPathway analysisFunctional studiesUnaffected carriersZebrafish modelAPOEe4 alleleProtein levelsBiallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
Chelban V, Aksnes H, Maroofian R, LaMonica L, Seabra L, Siggervåg A, Devic P, Shamseldin H, Vandrovcova J, Murphy D, Richard A, Quenez O, Bonnevalle A, Zanetti M, Kaiyrzhanov R, Salpietro V, Efthymiou S, Schottlaender L, Morsy H, Scardamaglia A, Tariq A, Pagnamenta A, Pennavaria A, Krogstad L, Bekkelund Å, Caiella A, Glomnes N, Brønstad K, Tury S, Moreno De Luca A, Boland-Auge A, Olaso R, Deleuze J, Anheim M, Cretin B, Vona B, Alajlan F, Abdulwahab F, Battini J, İpek R, Bauer P, Zifarelli G, Gungor S, Kurul S, Lochmuller H, Da’as S, Fakhro K, Gómez-Pascual A, Botía J, Wood N, Horvath R, Ernst A, Rothman J, McEntagart M, Crow Y, Alkuraya F, Nicolas G, Arnesen T, Houlden H. Biallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications. Nature Communications 2024, 15: 2269. PMID: 38480682, PMCID: PMC10937998, DOI: 10.1038/s41467-024-46354-0.Peer-Reviewed Original ResearchConceptsPrimary familial brain calcificationDisease-causing mechanismsLoss-of-functionReduced surface levelsTransmembrane proteinsNAA60Progressive movement disorderBiochemical explanationAcetylation capacityPhosphate uptakeGenesBrain calcificationVariantsProteinHeterogeneous disorderSLC20A2Neurobiological functionsSurface levelMovement disordersCalcium depositionCells
2023
Drebrin Regulates Collateral Axon Branching in Cortical Layer II/III Somatosensory Neurons
Dorskind J, Sudarsanam S, Hand R, Ziak J, Amoah-Dankwah M, Guzman-Clavel L, Soto-Vargas J, Kolodkin A. Drebrin Regulates Collateral Axon Branching in Cortical Layer II/III Somatosensory Neurons. Journal Of Neuroscience 2023, 43: 7745-7765. PMID: 37798130, PMCID: PMC10648559, DOI: 10.1523/jneurosci.0553-23.2023.Peer-Reviewed Original ResearchConceptsLoss-of-functionCollateral axonal branchingMolecular mechanismsF-actin bundlesStructure-function analysisCircuit formationAxon collateral branchesCortical circuit formationAxonal branchesPyramidal excitatory neuronsLoss-of-function experimentsFemale mouse modelProtein domainsF-actinCortical neuronal morphologyLaminar-specific mannerBranch initiationGene expressionSynaptic partnersSingle-cell labelingAxonal protrusionsDrebrinExcitatory neuronsSomatosensory neuronsDBN1
2021
Functional and behavioral effects of de novo mutations in calcium-related genes in patients with bipolar disorder
Nakamura T, Nakajima K, Kobayashi Y, Itohara S, Kasahara T, Tsuboi T, Kato T. Functional and behavioral effects of de novo mutations in calcium-related genes in patients with bipolar disorder. Human Molecular Genetics 2021, 30: 1851-1862. PMID: 34100076, PMCID: PMC8444452, DOI: 10.1093/hmg/ddab152.Peer-Reviewed Original ResearchConceptsLoss-of-functionBipolar disorderDe novo mutationsCalcium-related genesGenetic architectureAnimal models of bipolar disorderModel of bipolar disorderGenetic architecture of bipolar disorderStudies of bipolar disorderIdentified de novo mutationsLoss-of-function mutationsProtein-altering mutationsMutant miceSchizoaffective disorderBipolar IBehavioral effectsTruncated proteinBehavioral alterationsInhibit endocytosisDiminished attentionKnock-in mouse lineCellular functionsMental illnessBehavioral screeningEHD1
2018
Quantitative evaluation of incomplete preweaning lethality in mice by using the CRISPR/Cas9 system
Nakamura T, Nakajima K, Ohnishi T, Yoshikawa T, Nakanishi M, Takumi T, Tsuboi T, Kato T. Quantitative evaluation of incomplete preweaning lethality in mice by using the CRISPR/Cas9 system. Scientific Reports 2018, 8: 16025. PMID: 30375401, PMCID: PMC6207718, DOI: 10.1038/s41598-018-34270-5.Peer-Reviewed Original ResearchConceptsInternational Mouse Phenotyping ConsortiumLoss-of-functionGenome-edited micePreweaning lethalityDisease-related genesFrameshift alleleHomozygous KO miceIMPC dataMolecular biology techniquesGenome editingMouse mutantsIncomplete penetranceCRISPR/Cas9 systemGenesAssociated with lethalityEhd1 geneMouse phenotypeHomozygous knockout miceMice mutantsCRISPR/Cas9Cell linesMutantsBiology techniquesAllelesKO mice
2013
Characterization of Three Vasopressin Receptor 2 Variants: An Apparent Polymorphism (V266A) and Two Loss-of-Function Mutations (R181C and M311V)
Armstrong S, Seeber R, Ayoub M, Feldman B, Pfleger K. Characterization of Three Vasopressin Receptor 2 Variants: An Apparent Polymorphism (V266A) and Two Loss-of-Function Mutations (R181C and M311V). PLOS ONE 2013, 8: e65885. PMID: 23762448, PMCID: PMC3675069, DOI: 10.1371/journal.pone.0065885.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAquaporin 2Arginine VasopressinArrestinsbeta-ArrestinsChlorocebus aethiopsCOS CellsCyclic AMPDiabetes Insipidus, NephrogenicGene Expression RegulationGenetic Diseases, X-LinkedGTP-Binding Protein alpha Subunits, GsHEK293 CellsHumansInappropriate ADH SyndromeInositol PhosphatesMutationPolymorphism, GeneticReceptors, VasopressinSignal TransductionConceptsNephrogenic diabetes insipidusArginine vasopressinWild-type receptorAquaporin-2 water channelsActivation of Gs proteinsIncreased inositol phosphate productionPartial agonismVasopressin V2 receptorInositol phosphate accumulationGain-of-function mutationsIncreased cAMP levelsBRET assayInositol phosphate productionLoss-of-function mutationsNephrogenic syndromeV2R mutationsLoss-of-functionDiabetes insipidusMutant V2RV2 receptorsCAMP accumulationMilder phenotypePosterior pituitaryB-arrestinControls water homeostasis
1999
The Cadherin-Catenin System: Implications for Growth and Differentiation of Endocrine Tissues
Pötter E, Bergwitz C, Brabant G. The Cadherin-Catenin System: Implications for Growth and Differentiation of Endocrine Tissues. Endocrine Reviews 1999, 20: 207-239. PMID: 10204118, DOI: 10.1210/edrv.20.2.0362.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsCadherin-catenin systemBeta-catenin/TCF4 complexComplex signal transduction pathwaysCell-cell adhesionNormal cell functionSignal transduction pathwaysLoss-of-functionRegulate cellular differentiationActivation of oncogenesEpigenetic mechanismsExtracellular modulatorsTransduction pathwaysTCF4 complexPosttranscriptional eventsCellular differentiationEndocrine tissuesIntracellular signalingGenetic mouse modelsProcess of tumorigenesisCadherin-cateninsSomatic gene mutationsPreservation of tissue integrityGene silencingCell adhesionC-Myc
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