Contribution of GABA-A receptor subunit deletions to Angelman syndrome pathophysiology
Contribution of GABA-A receptor subunit deletions to Angelman syndrome pathophysiology
批准号:
10391880
负责人:
Eric S Levine
金额:
$45.1万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-20 至 2025-02-28
关键词:
AffectAllelesAngelman SyndromeAnimal ModelAnimalsAntisense OligonucleotidesBehavioralBrainCell LineChromosome DeletionClustered Regularly Interspaced Short Palindromic RepeatsCognitiveCognitive deficitsDataDevelopmentElectrophysiology (science)EpilepsyFunctional disorderGABA ReceptorGABA-A ReceptorGene ClusterGene ExpressionGene MutationGenesGeneticGoalsHumanIncidenceIndividualInhibitory SynapseIntellectual functioning disabilityKnock-outLightMeasuresModelingMolecularMonitorMotorMotor AtaxiasMutationNeurodevelopmental DisorderNeuronsPatientsPhenotypePhysiologicalPopulationPredispositionPrevalencePropertyResourcesRodentRoleSeizuresSeveritiesSignal TransductionSpeechSynapsesSynaptic TransmissionSyndromeTestingUBE3A geneautism spectrum disorderdevelopmental diseaseexperimental studygenome editingimprintinduced pluripotent stem cellinnovationinterestknock-downloss of function mutationmotor deficitmulti-electrode arraysneurogeneticsneuronal excitabilitynew therapeutic targetnovelnovel therapeuticspatch clamppatient subsetsreceptorsynaptic inhibitiontherapeutic developmenttooltransmission processubiquitin-protein ligase
中文摘要
项目总结
染色体15q11-q13缺失的个体患有Angelman综合征(AS),这是一种神经遗传性疾病
智力障碍以智力残疾、运动性共济失调、失语和癫痫为特征的发育障碍这个
负责AS的特定基因编码泛素蛋白连接酶UBE3A,尽管
区域也被删除。AS也可能是由于UBE3A功能突变的丧失而导致的,UBE3A使另一方免于死亡
基因位于该区域。UBE3A突变患者通常具有较轻微的表型,尤其是
关于癫痫和癫痫发作。这表明,除了UBE3A外,该区域其他基因的丢失,
可能与重度癫痫患者的表型缺失有关。特别是,一组基因
编码三个GABAA受体亚基的区域位于AS中通常缺失的区域。减少表达
这些亚基中的一种与几种人类神经发育障碍有关,如Angelman
综合症、癫痫的某些症状形式和自闭症。我们假设GABRB3基因的半合子丢失,
GABRA5和/或GABRG3结合UBE3A表达的缺失,导致神经元过度兴奋和
增强人类个体的癫痫易感性。我们将通过比较
AS患者因突变和缺失而产生的AS神经元的生理表型。我们将使用反义
用寡核苷酸方法确定是否下调这些GABA受体亚单位的表达
UBE3A缺陷系将导致AS缺失型患者来源的神经元兴奋性增加。
这些研究将阐明AS发作的细胞机制,并确定AS的靶点
开发新的治疗方法。
英文摘要
PROJECT SUMMARY
Individuals with a deletion of chromosome 15q11-q13 suffer from Angelman syndrome (AS), a neurogenetic
developmental disorder characterized by intellectual disability, motor ataxia, absent speech, and seizures. The
specific gene that is responsible for AS encodes the ubiquitin protein ligase UBE3A, although other genes in the
region are also deleted. AS can also result from loss of function mutations of UBE3A, which spares the other
genes located in the region. UBE3A mutation AS patients typically have a milder phenotype, especially with
regard to epilepsy and seizures. This suggests that the loss of other genes in the region, in addition to UBE3A,
likely contribute to the severe epilepsy phenotype in deletion AS patients. In particular, a cluster of genes
encoding three GABAA receptor subunits is located within the region typically deleted in AS. Reduced expression
of these subunits has been implicated in several human neurodevelopmental disorders such as Angelman
syndrome, certain syndromic forms of epilepsy, and autism. We hypothesize that hemizygous loss of GABRB3,
GABRA5, and/or GABRG3, in conjunction with loss of UBE3A expression, causes neuronal hyperexcitability and
enhanced seizure susceptibility in human AS individuals. We will test this hypothesis by comparing the
physiological phenotype of AS neurons derived from mutation and deletion AS patients. We will use antisense
oligonucleotide approaches to determine if knocking down expression of these GABA receptor subunits in a
UBE3A deficient line will confer the increased excitability seen in neurons derived from AS deletion patients.
These studies will shed light on the cellular mechanisms responsible for seizures in AS and identify targets for
development of novel therapeutics.
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