Elucidating the molecular pathology of DEPDC5 mutation induced mTOR-hyperactivation associated with epilepsy and autism spectrum disorder
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE240337 | GEO | 2024/12/31
REPOSITORIES: GEO
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Project description:Elucidating the molecular pathology of DEPDC5 mutation induced mTOR-hyperactivation associated with epilepsy and autism spectrum disorder
| PRJNA1003403 | ENA
Project description:Homozygous recessive mutations in the PRICKLE1 gene were first described in three consanguineous families with myoclonic epilepsy. Subsequent studies have identified neurological abnormalities in humans and animal models with both heterozygous and homozygous mutations in PRICKLE1 orthologs. We describe a 7-year-old with a novel de novo missense mutation in PRICKLE1 associated with epilepsy, autism spectrum disorder and global developmental delay.
| S-EPMC6251753 | biostudies-literature
Project description:Mammalian target of rapamycin (mTOR) is a key regulator in various cellular processes, including cell growth, gene expression, and synaptic functions. Autism spectrum disorder (ASD) is frequently accompanied by monogenic disorders, such as tuberous sclerosis complex, phosphatase and tensin homolog tumor hamartoma syndrome, neurofibromatosis 1, and fragile X syndrome, in which mTOR is hyperactive. Mutations in the genes involved in the mTOR-mediated signaling pathway have been identified in some cases of syndromic ASD. Evidences indicate a pathogenic role for hyperactive mTOR-mediated signaling in ASD associated with these monogenic disorders, and mTOR inhibitors are a potential pharmacotherapy for ASD. Abnormal synaptic transmission through metabotropic glutamate receptor 5 may underlie in a part of ASD associated with hyperactive mTOR-mediated signaling. In this review, the relationship between mTOR and ASD is discussed.
| S-EPMC5070418 | biostudies-literature
Project description:Autism spectrum disorder (ASD) is a behaviorally defined disorder affecting 1 in 68 children. Currently, there is no known cause for the majority of ASD cases nor are there physiological diagnostic tools or biomarkers to aid behavioral diagnosis. Whole-genome linkage studies, genome-wide association studies, copy number variation screening, and SNP analyses have identified several ASD candidate genes, but which vary greatly among individuals and family clusters, suggesting that a variety of genetic mutations may result in a common pathology or alter a common mechanistic pathway. The Akt/mammalian target of rapamycin (mTOR) pathway is involved in many cellular processes including synaptic plasticity and immune function that can alter neurodevelopment. In this study, we examined the activity of the Akt/mTOR pathway in cells isolated from children with ASD and typically developing controls. We observed higher activity of mTOR, extracellular receptor kinase, and p70S6 kinase and lower activity of glycogen synthase kinase 3 (GSK3)α and tuberin (TSC2) in cells from children with ASD. These data suggest a phosphorylation pattern indicative of higher activity in the Akt/mTOR pathway in children with general/idiopathic ASD and may suggest a common pathological pathway of interest for ASD.
| S-EPMC5350147 | biostudies-literature
Project description:Autism spectrum disorder (ASD) is a neurodevelopmental disease that may involve various brain abnormalities. However, there are few large epidemiological studies on the relation between epilepsy and ASD in terms of different genders and ages. This study aimed to evaluate the relation between epilepsy and ASD based on 74,251 Chinese children aged 3-12 years who were recruited from kindergartens and primary schools in China. ASD was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-V), and verification of epilepsy was based on medical records. The enrolled children diagnosed with ASD were examined by magnetic resonance imaging (MRI) and took genetic tests to rule out other neurological and congenital diseases. The raw odds ratio (OR) was 60.53 [95% confidence interval (CI) = 37.80-96.92, P < 0.01] for epilepsy and ASD, and the adjusted OR was 38.99 (95% CI = 20.70-73.41, P < 0.01) after controlling for the confounders. Moreover, the adjusted OR was significantly higher in girls (OR = 45.26, 95% CI = 16.42-124.76, P < 0.01) than in boys (OR = 32.64, 95% CI = 14.33-74.34, P < 0.01). Among children with younger age, the adjusted OR was the highest (OR = 75.12, 95% CI = 22.80-247.48.16, P < 0.01). These findings suggest that epilepsy might be closely linked to the development of ASD, especially for early-onset epilepsy and among girls.
| S-EPMC6751887 | biostudies-literature
Project description:ObjectiveTo clarify the complex mechanism underlying epileptogeneis, a novel animal model was generated.MethodsIn our previous research, we have generated a melanocyte-lineage mTOR hyperactivation mouse model (Mitf-M-Cre Tsc2 KO mice; cKO mice) to investigate mTOR pathway in melanogenesis regulation, markedly reduced skin pigmentation was observed. Very unexpectedly, spontaneous recurrent epilepsy was also developed in this mouse model.ResultsCompared with control littermates, no change was found in either brain size or brain mass in cKO mice. Hematoxylin staining revealed no obvious aberrant histologic features in the whole brains of cKO mice. Histoimmunofluorescence staining and electron microscopy examination revealed markedly increased mTOR signaling and hyperproliferation of mitochondria in cKO mice, especially in the hippocampus. Furthermore, rapamycin treatment reversed these abnormalities.ConclusionsThis study suggests that our melanocyte-lineage mTOR hyperactivation mouse is a novel animal model of epilepsy, which may promote the progress of both epilepsy and neurophysiology research.
| S-EPMC6980560 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-02-27 | GSE111176 | GEO
Project description:ObjectivesTo estimate the prevalence of epilepsy in children with Autism Spectrum Disorder (ASD) and to determine the demographic and clinical characteristics of children with ASD and epilepsy in a large patient population.MethodsCross-sectional study using four samples of children with ASD for a total of 5,815 participants with ASD. The prevalence of epilepsy was estimated from a population-based sample. Children with and without epilepsy were compared on demographic and clinical characteristics. Multivariate logistic regression was used to examine the association between demographic and clinical characteristics and epilepsy.ResultsThe average prevalence of epilepsy in children with ASD 2-17 years was 12.5%; among children aged 13 years and older, 26% had epilepsy. Epilepsy was associated with older age, lower cognitive ability, poorer adaptive and language functioning, a history of developmental regression and more severe ASD symptoms. The association between epilepsy and the majority of these characteristics appears to be driven by the lower IQ of participants with epilepsy. In a multivariate regression model, only age and cognitive ability were independently associated with epilepsy. Children age 10 or older had 2.35 times the odds of being diagnosed with epilepsy (p<.001) and for a one standard deviation increase in IQ, the odds of having epilepsy decreased by 47% (p<.001).ConclusionThis is among the largest studies to date of patients with ASD and co-occurring epilepsy. Based on a representative sample of children with ASD, the average prevalence of epilepsy is approximately 12% and reaches 26% by adolescence. Independent associations were found between epilepsy and older age and lower cognitive ability. Other risk factors, such as poor language and developmental regression, are not associated with epilepsy after controlling for IQ. These findings can help guide prognosis and alert clinicians to patients with ASD who are at increased risk for epilepsy.
| S-EPMC3701630 | biostudies-literature
Project description:Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder whose pathogenesis is still unclear. MicroRNAs (miRNAs) are a kind of endogenous small non-coding RNAs that play important roles in the post-transcriptional regulation of genes. Recent researches show that miRNAs are edited in multiple ways especially in central nervous systems. A-to-I editing of RNA catalyzed by Adenosine deaminases acting on RNA (ADARs) happens intensively in brain and is also noticed in other organs and tissues. Although miRNAs are widely edited in human brain, miRNA editing in ASD is still largely unexplored. In order to reveal the editing events of miRNAs in ASD, we analyzed 131 miRNA-seq samples from 8 different brain regions of ASD patients and normal controls. We identified 834 editing sites with significant editing levels, of which 70 sites showed significantly different editing levels in the superior frontal gyrus samples of ASD patients (ASD-SFG) when compared with those of control samples. The editing level of an A-to-I editing site in hsa-mir-376a-1 (hsa-mir-376a-1_9_A_g) in ASD-SFG is higher than that of normal controls, and the difference is exaggerated in individuals under 10 years. The increased expression of ADAR1 is consistent with the increased editing level of hsa-mir-376a-1_9_A_g in ASD-SFG samples compared to normal SFG samples. Furthermore, we verify that A-to-I edited hsa-mir-376a-5p directly represses GPR85 and NAPB, which may contribute to the abnormal neuronal development of ASD patients. These results provide new insights into the mechanism of ASD.
| S-EPMC9895120 | biostudies-literature
Project description:RationaleCUL3 (OMIM: 603136) encodes cullin-3, a core component of ubiquitin E3 ligase. Existing medical research suggests that CUL3 mutations are closely related to neurodevelopmental disorder with or without autism or seizures (neurodevelopmental disorder with autism and seizures, OMIM: 619239). However, the number of published case reports of autism spectrum disorder due to CUL3 gene mutations is limited.Patient concernA four-year-old Chinese girl presented with generalized epilepsy, and then exhibited developmental regression, including loss of her speaking ability, eye contact aversion, and stereotyped behavior.DiagnosesWhole-exome sequencing identified a nonsense mutation in the CUL3 gene, being c.2065A > T (p.Lys689*); no previous similar case was reported. The final diagnosis was autism, epilepsy, and motor growth retardation.InterventionIn order to improve quality of life of the patient, she was provided with exercise rehabilitation training and autism behavioral guidance therapy for 3 months.OutcomesThe patient's exercise capacity had improved, and improvements in autism symptoms were not obvious.LessonsFor clinicians, patients with developmental regression accompanied with concurrent epilepsy and autism spectrum disorder should be advised that relevant genetic tests are necessary to clarify the diagnosis.
| S-EPMC10082260 | biostudies-literature