Ube3a/E6AP is involved in a subset of MeCP2 functions

Kim, Soeun; Chahrour, Maria H.; Ben‐Shachar, Shay; Lim, Janghoo

doi:10.1016/j.bbrc.2013.06.036

Cited by 19 publications

(12 citation statements)

References 31 publications

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“…UBE3A may repress Cbln1 through its transcriptional co-regulatory functions 10,31,32 . For example, UBE3A physically interacts with MECP2 33 (methyl CpG-binding protein 2, deleted in Rett syndrome) that represses a subset of genes through interactions with the NCoR repressor complex ( n uclear receptor co - r epressor) 34 . Seizures upregulate the transcriptional repressor REST ( RE -1 s ilencing t ranscription factor) in hippocampus 35,36 as well as in VTA (Extended Data Fig.…”

Section: Discussionmentioning

confidence: 99%

Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1

Krishnan

Stoppel

Nong

et al. 2017

Nature

133

137

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SummaryMaternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant autism linked to increased gene dosages of UBE3A, which both possesses ubiquitin-ligase and transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus down-regulates glutamatergic synapse organizer cerebellin-1 (Cbln1) that is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases of UBE3A. This Ube3a-seizure synergy maps to glutamate neurons of the midbrain ventral tegmental area (VTA) where Cbln1 deletions impair sociability and weaken glutamatergic transmission. We provide preclinical evidence that viral-vector-based chemogenetic activations of, or Cbln1 restorations in VTA glutamatergic neurons rescues sociability deficits induced by Ube3a and/or seizures. Our results suggest a gene × seizure interaction in VTA glutamatergic neurons that impairs sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes.

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Section: Discussionmentioning

confidence: 99%

Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1

Krishnan

Stoppel

Nong

et al. 2017

Nature

133

137

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“…Recently proposed as a substrate for E6-AP is sacsin,104 defects of which cause a form of spastic ataxia;106 given the ataxic gait in AS, sacsin is an attractive target. There is also mounting evidence that UBE3A and methyl CpG binding protein 2 interact to regulate the expression of target genes 107. Recently, a role for E6-AP in Golgi acidification and protein sialylation was proposed 108…”

Section: Molecular Pathogenesismentioning

confidence: 99%

Angelman syndrome: review of clinical and molecular aspects

Bird

2014

TACG

179

155

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“Angelman syndrome” (AS) is a neurodevelopmental disorder whose main features are intellectual disability, lack of speech, seizures, and a characteristic behavioral profile. The behavioral features of AS include a happy demeanor, easily provoked laughter, short attention span, hypermotoric behavior, mouthing of objects, sleep disturbance, and an affinity for water. Microcephaly and subtle dysmorphic features, as well as ataxia and other movement disturbances, are additional features seen in most affected individuals. AS is due to deficient expression of the ubiquitin protein ligase E3A (UBE3A) gene, which displays paternal imprinting. There are four molecular classes of AS, and some genotype–phenotype correlations have emerged. Much remains to be understood regarding how insufficiency of E6-AP, the protein product of UBE3A, results in the observed neurodevelopmental deficits. Studies of mouse models of AS have implicated UBE3A in experience-dependent synaptic remodeling.

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“…MPP1 (signal transduction, neuronal homeostasis) and IGF2 (cell proliferation) were identified in a transcriptomics expression study to be strongly overexpressed in a study with human lymphoblastoid cells of Rett patients and controls [91]. MECP2 interacts with E6AP, the protein of the UBE3A gene and they are regulating the expression of several target genes [92]. GRID1 encodes for glutamate D1 receptor (GluD1) and is downregulated in the absence of functional MECP2 [83].…”

Section: The Most Important Metabolites Genes and Pathways Affected mentioning

confidence: 99%

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

Ehrhart

Coort

Cirillo

et al. 2016

Orphanet J Rare Dis

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Rett syndrome (RTT) is a rare disease but still one of the most abundant causes for intellectual disability in females. Typical symptoms are onset at month 6–18 after normal pre- and postnatal development, loss of acquired skills and severe intellectual disability. The type and severity of symptoms are individually highly different. A single mutation in one gene, coding for methyl-CpG-binding protein 2 (MECP2), is responsible for the disease. The most important action of MECP2 is regulating epigenetic imprinting and chromatin condensation, but MECP2 influences many different biological pathways on multiple levels although the molecular pathways from gene to phenotype are currently not fully understood. In this review the known changes in metabolite levels, gene expression and biological pathways in RTT are summarized, discussed how they are leading to some characteristic RTT phenotypes and therefore the gaps of knowledge are identified. Namely, which phenotypes have currently no mechanistic explanation leading back to MECP2 related pathways? As a result of this review the visualization of the biologic pathways showing MECP2 up- and downstream regulation was developed and published on WikiPathways which will serve as template for future omics data driven research. This pathway driven approach may serve as a use case for other rare diseases, too.

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Ube3a/E6AP is involved in a subset of MeCP2 functions

Cited by 19 publications

References 31 publications

Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1

Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1

Angelman syndrome: review of clinical and molecular aspects

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

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