Dataset Information

Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1.

ABSTRACT: Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant type of autism linked to increased gene dosages of UBE3A, which encodes a ubiquitin ligase with transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus downregulates the glutamatergic synapse organizer Cbln1, which is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in mice with asymptomatic increases in 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 activation of, or restoration of Cbln1 in, VTA glutamatergic neurons reverses the sociability deficits induced by Ube3a and/or seizures. Our results suggest that gene and seizure interactions in VTA glutamatergic neurons impair sociability by downregulating Cbln1, a key node in the expanding protein interaction network of autism genes.

SUBMITTER: Krishnan V

PROVIDER: S-EPMC5364052 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1.

Krishnan Vaishnav V Stoppel David C DC Nong Yi Y Johnson Mark A MA Nadler Monica J S MJ Ozkaynak Ekim E Teng Brian L BL Nagakura Ikue I Mohammad Fahim F Silva Michael A MA Peterson Sally S Cruz Tristan J TJ Kasper Ekkehard M EM Arnaout Ramy R Anderson Matthew P MP

Nature 20170315 7646

Maternally inherited 15q11-13 chromosomal triplications cause a frequent and highly penetrant type of autism linked to increased gene dosages of UBE3A, which encodes a ubiquitin ligase with transcriptional co-regulatory functions. Here, using in vivo mouse genetics, we show that increasing UBE3A in the nucleus downregulates the glutamatergic synapse organizer Cbln1, which is needed for sociability in mice. Epileptic seizures also repress Cbln1 and are found to expose sociability impairments in m ...[more]

PMID: 28297715

Similar Datasets

Project description:Background15q11-13 region is one of the most complex chromosomal regions in the human genome. UBE3A is an important candidate gene of autism spectrum disorder (ASD), which located at the 15q11-13 region and encodes ubiquitin-protein ligase E3A. Previous studies about UBE3A gene and ASD have shown inconsistent results and few studies were performed in Chinese population. This study aimed to detect the genetic mutations of UBE3A gene in Chinese Han population with ASD and analyze genetic association between these variants and ASD.MethodsThe samples consisted of 192 patients with autism according to the DSM-IV diagnostic criteria and 192 healthy controls. We searched for mutations at coding sequence (CDS) regions and their adjacent non-coding regions of UBE3A gene using the high resolution melting (HRM) and Sanger sequencing methods. We further increased sample size to validate the detected variants using HRM and conducted association analysis between case and control groups.ResultsA known single nucleotide polymorphism (T > C, rs150331504) located at the CDS4 and a known 5 bp insertion/deletion variation (AACTC+/-, rs71127053) located at the intron region of the upstream 288 bp of the CDS2 of UBE3A gene were detected using Sanger sequencing method. The ASD samples of case group were 391 for rs71127053, 384 for rs150331504 and 384 healthy controls, which were used to make an association analysis. The results of association analysis suggested that there were no significant difference about the allele and genotype frequencies of rs71127053 and rs150331504 between case and control groups after extending the sample size. Besides, rs150331504 is a synonymous mutation and we compared the secondary structure and minimum free energy (MFE) of mRNA harboring the allele T or C of rs150331504 using RNAfold software. We found that the centroid secondary structure apparently differs along with the polymorphisms of rs150331504 T > C, the results suggested that this variant might change the secondary structure of mRNA of UBE3A gene. We did not detect mutations in other coding regions of UBE3A gene.ConclusionsThese findings showed that UBE3A gene might not be a major disease gene in Chinese ASD cases.

Dataset Information

Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1.

Publications

Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets