Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism.

ABSTRACT: Substantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice by using chromosome engineering to generate a 6.3 Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. An increased MBII52 snoRNA within the duplicated region, affecting the serotonin 2c receptor (5-HT2cR), correlates with altered intracellular Ca(2+) responses elicited by a 5-HT2cR agonist in neurons of mice with a paternal duplication. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will facilitate forward genetics of developmental brain disorders and serve as an invaluable tool for therapeutic development.

SUBMITTER: Nakatani J

PROVIDER: S-EPMC3710970 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Skeletal Site-specific Changes in Bone Mass in a Genetic Mouse Model for Human 15q11-13 Duplication Seen in Autism.

Project description:Children suffering from autism have been reported to have low bone mineral density and increased risk for fracture, yet the cellular origin of the bone phenotype remains unknown. Here we have utilized a mouse model of autism that duplicates 6.3?Mb region of chromosome 7 (Dp/+) corresponding to a region of chromosome 15q11-13, duplication of which is recurrent in humans to characterize the bone phenotype. Paternally inherited Dp/+ (patDp/+) mice showed expected increases in the gene expression in bone, normal postnatal growth and body weight acquisition compared to the littermate controls. Four weeks-old patDp/+ mice develop a low bone mass phenotype in the appendicular but not the axial skeleton compared to the littermate controls. This low bone mass in the mutant mice was secondary to a decrease in the number of osteoblasts and bone formation rate while the osteoclasts remained relatively unaffected. Further in vitro cell culture experiments and gene expression analysis revealed a major defect in the proliferation, differentiation and mineralization abilities of patDp/+ osteoblasts while osteoclast differentiation remained unchanged compared to controls. This study therefore characterizes the structural and cellular bone phenotype in a mouse model of autism that can be further utilized to investigate therapeutic avenues to treat bone fractures in children with autism.

| S-EPMC5575059 | biostudies-literature

Upregulated 5-HT1A receptor-mediated currents in the prefrontal cortex layer 5 neurons in the 15q11-13 duplication mouse model of autism.

Project description:Serotonin (5-HT) is a well-known modulator of behavioral, physiological, and emotional functions of the forebrain region. We recently discovered alterations of serotonergic synaptic modulations in both, the prefrontal cortex (PFC) and the somatosensory cortex, in the 15q dup mouse model of autism spectrum disorder (ASD). To further understand the roles of the 5-HT system implicated in developmental disorders such as ASD, comparison with model animals exhibiting different phenotypes may be useful. In this study, we investigated the relationship between sociability and the magnitude of 5-HT1A receptor (5-HT1AR) activation-induced outward currents from layer 5 pyramidal neurons in the PFC, because a mouse model of Williams-Beuren syndrome (WBS; another developmental disorder exhibiting low innate anxiety and high sociability) reportedly showed larger 5-HT-induced currents. To investigate whether the 5-HT1AR activation-induced outward currents are involved in the endophenotype determination of social behavior, we examined 15q dup mice with a phenotype opposite to WBS. We found 5-HT elicited significantly larger outward currents in 15q dup mice than in WT controls, regardless of sociability. In contrast, baclofen-induced GABAB receptor-mediated outward currents were not significantly different between genotypes, although GABAB receptor was coupled to Gi/o as well as 5-HT1A. Further, we found the larger 5-HT1AR-mediated currents in 15q dup mice did not affect the magnitude of inhibitory action of NMDA receptor functions. Taken together, our results provide a potential physiological hallmark for developmental disorders that may involve the imbalance of the neuronal circuity in the PFC.

| S-EPMC7444243 | biostudies-literature

Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number.

Project description:Chromosome 15q11-13 contains a cluster of imprinted genes essential for normal mammalian neurodevelopment. Deficiencies in paternal or maternal 15q11-13 alleles result in Prader-Willi or Angelman syndromes, respectively, and maternal duplications lead to a distinct condition that often includes autism. Overexpression of maternally expressed imprinted genes is predicted to cause 15q11-13-associated autism, but a link between gene dosage and expression has not been experimentally determined in brain.Postmortem brain tissue was obtained from a male with 15q11-13 hexasomy and a female with 15q11-13 tetrasomy. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to measure 10 15q11-13 transcripts in maternal 15q11-13 duplication, Prader-Willi syndrome, and control brain samples. Southern blot, bisulfite sequencing and fluorescence in situ hybridisation were used to investigate epigenetic mechanisms of gene regulation.Gene expression and DNA methylation correlated with parental gene dosage in the male 15q11-13 duplication sample with severe cognitive impairment and seizures. Strikingly, the female with autism and milder Prader-Willi-like characteristics demonstrated unexpected deficiencies in the paternally expressed transcripts SNRPN, NDN, HBII85, and HBII52 and unchanged levels of maternally expressed UBE3A compared to controls. Paternal expression abnormalities in the female duplication sample were consistent with elevated DNA methylation of the 15q11-13 imprinting control region (ICR). Expression of non-imprinted 15q11-13 GABA receptor subunit genes was significantly reduced specifically in the female 15q11-13 duplication brain without detectable GABRB3 methylation differences.Our findings suggest that genetic copy number changes combined with additional genetic or environmental influences on epigenetic mechanisms impact outcome and clinical heterogeneity of 15q11-13 duplication syndromes.

| S-EPMC2634820 | biostudies-literature

Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice.

Project description:Serotonin is a critical modulator of cortical function, and its metabolism is defective in autism spectrum disorder (ASD) brain. How serotonin metabolism regulates cortical physiology and contributes to the pathological and behavioral symptoms of ASD remains unknown. We show that normal serotonin levels are essential for the maintenance of neocortical excitation/inhibition balance, correct sensory stimulus tuning, and social behavior. Conversely, low serotonin levels in 15q dup mice (a model for ASD with the human 15q11-13 duplication) result in impairment of the same phenotypes. Restoration of normal serotonin levels in 15q dup mice revealed the reversibility of a subset of ASD-related symptoms in the adult. These findings suggest that serotonin may have therapeutic potential for discrete ASD symptoms.

| S-EPMC5479676 | biostudies-literature

Transmission disequilibrium testing of the chromosome 15q11-q13 region in autism.

Project description:Evidence implicates the serotonin transporter gene (SLC6A4) and the 15q11-q13 genes as candidates for autism as well as restricted repetitive behavior (RRB). We conducted dense transmission disequilibrium mapping of the 15q11-q13 region with 93 single nucleotide polymorphisms (SNPs) in 86 strictly defined autism trios and tested association between SNPs and autism using the transmission disequilibrium test (TDT). As exploratory analyses, parent-of-origin effects were examined using likelihood-ratio tests (LRTs) and genotype-phenotype associations for specific RRB using the Family-Based Association Test (FBAT). Additionally, gene-gene interactions between nominally associated 15q11-q13 variants and 5-HTTLPR, the common length polymorphism of SLC6A4, were examined using conditional logistic regression (CLR). TDT revealed nominally significant transmission disequilibrium between autism and five SNPs, three of which are located within close proximity of the GABA(A) receptor subunit gene clusters. Three SNPs in the SNRPN/UBE3A region had marginal imprinting effects. FBAT for genotype-phenotype relations revealed nominally significant association between two SNPs and one ADI-R subdomain item. However, both TDT and FBAT were not statistically significant after correcting for multiple comparisons. Gene-gene interaction analyses by CLR revealed additive genetic effect models, without interaction terms, fit the data best. Lack of robust association between the 15q11-q13 SNPs and RRB phenotypes may be due to a small sample size and absence of more specific RRB measurement. Further investigation of the 15q11-q13 region with denser genotyping in a larger sample set may be necessary to determine whether this region confers risk to autism, indicated by association, or to specific autism phenotypes.

| S-EPMC4095800 | biostudies-literature

Mice model for 15q11-13 duplication syndrome show late onset obesity and altered lipid metabolism

Project description:To investigate the gene expression change in the white adipose tissue (WAT) of patDp/+ mice compared with wild type mice, the whole genome microarray profiling was performed. Total RNA from WAT of young adult stage mice (9-10 weeks old) was extracted and subject to microarray analysis. Expression change of sfrp5 gene was further validated by real-time PCR, suggesting this gene might contribute to the obesity in patDp/+ mice.

2015-05-01 | GSE58191 | GEO

Mice model for 15q11-13 duplication syndrome show late onset obesity and altered lipid metabolism

2015-05-01 | E-GEOD-58191 | biostudies-arrayexpress

Transcription profiling of human lymphoblastoid cells from individuals with autism and duplication of 15q11-13autism with dup(15q)

Project description:gene expression profiles of lymphoblastoid cells from individuals with autism and duplication of 15q11-13 Experiment Overall Design: Cy5; each male with autism and dup(15q) Experiment Overall Design: Cy3; pool of 14 unrelated individuals.

2008-06-15 | E-GEOD-7315 | biostudies-arrayexpress

Variants in LRRC7 lead to intellectual disability, autism, aggression and abnormal eating behavior

Project description:Proximity labeling/BioID analysis of LRR7/Densin-180 293T cells were transfected with emty BioID vectors coding for LRR/BioID or full-length Densin-180/BioID fusion proteins. After treatment with Biotin,cells were lysed in RIPA(samples 1-6) or IP(samples 7-9)buffer. Biotinylated proteins were purified using strepavidin beads and processed for mass spectrodcopic analysis

2024-08-15 | PXD044289 | Pride

A case of 15q11-q13 duplication syndrome and literature review.

Project description:BackgroundThe chromosomal 15q11-q13 regions are structurally complex, and their abnormalities are associated with various neuropsychiatric disorders, including autism spectrum disorder (ASD), epilepsy, Angelman syndrome, and Prader-Willi syndrome.Case descriptionA 6-year-old child was admitted to the hospital as a result of an "epileptic status" showing ASD, intractable epilepsy, and total developmental retardation. Chromosome gene detection showed repetitive variation in the 15q11-q13 regions, and the video electroencephalogram was abnormal. Although children are currently given antiepileptic treatment and rehabilitation training, intermittent seizures can still occur.ConclusionThe clinical phenotypes of 15q11-q13 repetitive syndrome are complex, and vary in severity. Children with intractable epilepsy, ASD, and language and motor retardation should be considered to have this syndrome, which requires confirmation by multiplex ligation-dependent probe amplification and gene detection. These approaches can enable early rehabilitation treatment and improve the patients' quality of life.

| S-EPMC8413793 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data