Utilizing Causal X-Linked Intellectual Disability Variants to Gain Insight into the O-GlcNAc Transferase Enzyme
利用因果 X 连锁智力障碍变异来深入了解 O-GlcNAc 转移酶
基本信息
- 批准号:10607359
- 负责人:
- 金额:$ 4.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AcademiaAdaptive BehaviorsAddressAffectBindingBiochemicalBiologyCRISPR/Cas technologyCarbohydratesCatalytic DomainCell physiologyCellsCellular AssayChIP-seqCharacteristicsClinicalComplexCritical ThinkingDNADataDevelopmentDevelopmental GeneDisability phenotypeDiseaseEngineeringEnvironmentEnzymatic BiochemistryEnzymesExcisionGene ExpressionGene Expression RegulationGenesGenetic TranscriptionGlobal ChangeGlycobiologyGoalsHuman EngineeringKineticsLaboratoriesLeadLearningLinkMass Spectrum AnalysisMentorshipMetabolicMethylationMissense MutationModelingMutationN-terminalNeurodevelopmental DisabilityNeuronal DifferentiationNuclearNutrientO-GlcNAc transferaseOutcomePatientsPhenotypePositioning AttributePost-Translational Protein ProcessingProteinsRecombinantsResearchRoleSerineSyndromeTechnical ExpertiseTestingThreonineTranscriptional RegulationTransferaseUnited StatesUniversitiesVariantWestern BlottingWorkX-linked intellectual disabilitybasecareercasein kinase IIcausal variantchromatin remodelingdesigndifferential expressionembryonic stem cellexperienceglycosyltransferasehuman embryonic stem cellhuman malein vitro Assayinsightmalenerve stem cellneurodevelopmentnovelpeptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidaseprotein protein interactionrelating to nervous systemresponsesensorskillstranscriptome sequencingtranscriptomics
项目摘要
Summary:
Approximately 1 in 500 males in the United States are affected by X-Linked Intellectual Disability (XLID). Our
laboratory has previously characterized several mutations in the O-GlcNAc Transferase (OGT) gene that are
causal for a syndromal form of XLID and have recently discovered three novel missense mutations in the catalytic
domain with clinical collaborators. OGT is an essential glycosyltransferase that is solely responsible for the
addition of the post-translational modification beta-N-acetylglucosamine (O-GlcNAc) onto serines and threonines
of target nuclear and cytosolic proteins. OGT and O-GlcNAc have been implicated in a variety of cellular
processes and diseases including neurodevelopment, transcriptional regulation, and XLID. Previous work by our
lab biochemically characterized mutations in the Tetratricopeptide Repeat (TPR) domain of OGT, but a unifying
downstream effect on transcription regulation responsible for the XLID phenotype has yet to be elucidated. Given
both catalytic domain and TPR domain mutations are causal for XLID, our hypothesis is that both the novel
catalytic domain variants and previously described TPR domain variants cause a dysregulation of gene
expression by an inability to fully glycosylate key target proteins involved in transcriptional regulation due to a
loss of OGT targeting (TPR domain) or reduction in OGT catalytic efficiency (catalytic domain). This hypothesis
is supported by data demonstrating that TPR domain variants have altered transcription compared to wildtype
and that catalytic domain variants can be causal for XLID. To test our hypothesis, we will biochemically
characterize the novel catalytic domain variants, and we will determine changes to gene expression for both
catalytic domain variants and previously characterized TPR domain variants. Our lab is uniquely poised to
address this hypothesis due to our expertise in O-GlcNAc biology, previous work with XLID variants, and our
possession of Cas9-engineered male human embryonic stem cells expressing TPR domain variants of OGT. In
aim 1, we will use in vitro assays and whole cell assays to determine changes in the biochemical characteristics
of the novel catalytic domain variants including thermal stability, kinetic parameters, and impact on global O-
GlcNAc levels when expressed in cellulo. In aim 2, we will determine changes in gene expression between all
characterized variants as we differentiate CRISPR/Cas9-engineered human embryonic stem cells to neural
precursor cells. When combined with ChIP-Seq data, we can evaluate the impact of OGT variants on regulation
of gene expression. Based on preliminary data, we will also investigate Tet2 and HCF1 as potential OGT
interactors/substrates to explain the dysregulation of gene expression. These approaches will help elucidate how
variants deficient in different functions result in the same XLID neurodevelopmental phenotype in the patient.
Furthermore, this research will take place at the Complex Carbohydrate Research Center at the University of
Georgia under the direction of Dr. Lance Wells, that will provide the trainee an excellent environment to learn
general and specialized biochemical skills as well as critical thinking skills under exemplary mentorship.
简介:
项目成果
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