Involvement of myocyte enhancer factor 2c in the pathogenesis of autism spectrum disorder

Chaudhary, Rishabh; Agarwal, Vipul; Kaushik, Arjun Singh; Rehman, Mujeeba

doi:10.1016/j.heliyon.2021.e06854

Cited by 13 publications

(6 citation statements)

References 199 publications

(343 reference statements)

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“…These genes are ranked based on their confidence levels within their respective classes, offering insights into potential associations or relevance to syndromic and non-syndromic conditions. From the list of syndromic genes, many of them are associated with brain development or neuronal development syndromes (TRIP12 [44], NSD1 [45], CTNND2 [46], CADPS2 [47], MEF2C [48], SOX5 [49], and GRIP1 [50]). In contrast, most non-syndromic genes do not have a clear connection with the brain or neural development.…”

Section: Syndromic Test Resultsmentioning

confidence: 99%

Graph Node Classification to Predict Autism Risk in Genes

Bandara,

Riccardi

2024

Genes

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This study explores the genetic risk associations with autism spectrum disorder (ASD) using graph neural networks (GNNs), leveraging the Sfari dataset and protein interaction network (PIN) data. We built a gene network with genes as nodes, chromosome band location as node features, and gene interactions as edges. Graph models were employed to classify the autism risk associated with newly introduced genes (test set). Three classification tasks were undertaken to test the ability of our models: binary risk association, multi-class risk association, and syndromic gene association. We tested graph convolutional networks, Graph Sage, graph transformer, and Multi-Layer Perceptron (Baseline) architectures on this problem. The Graph Sage model consistently outperformed the other models, showcasing its utility in classifying ASD-related genes. Our ablation studies show that the chromosome band location and protein interactions contain useful information for this problem. The models achieved 85.80% accuracy on the binary risk classification, 81.68% accuracy on the multi-class risk classification, and 90.22% on the syndromic classification.

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Section: Syndromic Test Resultsmentioning

confidence: 99%

Graph Node Classification to Predict Autism Risk in Genes

Bandara,

Riccardi

2024

Genes

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Section: Discussionmentioning

confidence: 99%

“…MEF2C is a transcription factor widely associated with various NDDs (2,32,(49)(50)(51)(52). MEF2C is among the highest ASD risk genes (51) and is strongly linked to schizophrenia (32), and intellectual disability (52). Here we employ genetic, electrophysiological, and behavioral approaches in mice to explore how cell-type specific loss of function of Mef2c at different ages leads to synaptic and neural circuit changes capable of recapitulating NDD-associated behaviors.…”

Section: Discussionmentioning

confidence: 99%

Developmental disruption ofMef2cin Medial Ganglionic Eminence-derived cortical inhibitory interneurons impairs cellular and circuit function

Ward,

Nasrallah,

Tran

et al. 2024

Preprint

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Background: MEF2C is strongly linked to various neurodevelopmental disorders (NDDs) including autism, intellectual disability, schizophrenia, and attention-deficit/hyperactivity. Mice constitutively lacking one copy ofMef2c, or selectively lacking both copies ofMef2cin cortical excitatory neurons, display a variety of behavioral phenotypes associated with NDDs. The MEF2C protein is a transcription factor necessary for cellular development and synaptic modulation of excitatory neurons. MEF2C is also expressed in a subset of cortical GABAergic inhibitory neurons, but its function in those cell types remains largely unknown. Methods: Using conditional deletions of theMef2cgene in mice, we investigated the role of MEF2C in Parvalbumin-expressing Interneurons (PV-INs), the largest subpopulation of cortical GABAergic cells, at two developmental timepoints. We performed slice electrophysiology, in vivo recordings, and behavior assays to test how embryonic and late postnatal loss of MEF2C from GABAergic interneurons impacts their survival and maturation, and alters brain function and behavior. Results: Loss of MEF2C from PV-INs during embryonic, but not late postnatal, development resulted in reduced PV-IN number and failure of PV-INs to molecularly and synaptically mature. In association with these deficits, early loss of MEF2C in GABAergic interneurons lead to abnormal cortical network activity, hyperactive and stereotypic behavior, and impaired cognitive and social behavior. Conclusions: MEF2C expression is critical for the development of cortical GABAergic interneurons, particularly PV-INs. Embryonic loss of function of MEF2C mediates dysfunction of GABAergic interneurons, leading to altered in vivo patterns of cortical activity and behavioral phenotypes associated with neurodevelopmental disorders.

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“…Mutations of Mef2c are associated with the Mef2c haploinsufficiency syndrome, which is a severe developmental disorder associated with intellectual disabilities, developmental delay, lack of speech, stereotypic movements, limited walking abilities or the inability to walk, seizures, and poor eye contact [ 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. Mef2c is also linked to Rett syndrome or severe Rett-like encephalopathies as well as schizophrenia and autism spectrum disorders characterized by dysmorphic features and cerebral malformations [ 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. It is noteworthy in this context that heterozygous Mef2c mice display autism-related behaviors [ 74 ], similar to L1-heterozygous mice [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

The Cell Adhesion Molecule L1 Interacts with Methyl CpG Binding Protein 2 via Its Intracellular Domain

Loers

Kleene

Minguez

et al. 2022

IJMS

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Cell adhesion molecule L1 regulates multiple cell functions, and L1 deficiency is linked to several neural diseases. Recently, we have identified methyl CpG binding protein 2 (MeCP2) as a potential binding partner of the intracellular L1 domain. By ELISA we show here that L1’s intracellular domain binds directly to MeCP2 via the sequence motif KDET. Proximity ligation assay with cultured cerebellar and cortical neurons suggests a close association between L1 and MeCP2 in nuclei of neurons. Immunoprecipitation using MeCP2 antibodies and nuclear mouse brain extracts indicates that MeCP2 interacts with an L1 fragment of ~55 kDa (L1−55). Proximity ligation assay indicates that metalloproteases, β-site of amyloid precursor protein cleaving enzyme (BACE1) and ɣ-secretase, are involved in the generation of L1−55. Reduction in MeCP2 expression by siRNA decreases L1-dependent neurite outgrowth from cultured cortical neurons as well as the migration of L1-expressing HEK293 cells. Moreover, L1 siRNA, MeCP2 siRNA, or a cell-penetrating KDET-containing L1 peptide leads to reduced levels of myocyte enhancer factor 2C (Mef2c) mRNA and protein in cortical neurons, suggesting that the MeCP2/L1 interaction regulates Mef2c expression. Altogether, the present findings indicate that the interaction of the novel fragment L1−55 with MeCP2 affects L1-dependent functions, such as neurite outgrowth and neuronal migration.

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Involvement of myocyte enhancer factor 2c in the pathogenesis of autism spectrum disorder

Cited by 13 publications

References 199 publications

Graph Node Classification to Predict Autism Risk in Genes

Graph Node Classification to Predict Autism Risk in Genes

Developmental disruption ofMef2cin Medial Ganglionic Eminence-derived cortical inhibitory interneurons impairs cellular and circuit function

The Cell Adhesion Molecule L1 Interacts with Methyl CpG Binding Protein 2 via Its Intracellular Domain

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