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Transcriptome deviation in early neuronal stage of MBD5-Associated Neurodevelopmental Disorder (MAND)

ABSTRACT: Purpose: MBD5-Associated Neurodevelopmental Disorder (MAND) is an Autism Spectrum Disorder (ASD) disorder characterized by intellectual disability, motor delay, severe speech impairment and autism-like behavioral problems. The role of MBD5 in neurodevelopmental function remains largely undefined. In this study, we explored the neurodevelopmental phenotype of 2q23.1 deletion syndrome through creating neuronal progenitor stem cells (NPC) derived from 2q23.1 patients and conducting RNA-seq to identify the contributory altered gene and to expand our knowledge about gene network differences and possible interactions between the related disease pathways and ASD. Methods: Primary skin fibroblasts from three MAND patients and four control cases were converted into induced pluripotent stem cell (iPSC) lines by transient transfections of episomal plasmids. Directed differentiation of these iPSC to NPC was accomplished with monolayer culture protocol for two weeks. Results: The RNA-seq analysis identified 498 genome-wide significant (q < 0.05) differentially expressed gene in the patients derived NPC lines as a consequence of reduced MBD5 dosage. 25 ASD associated genes were included in the differentially expressed gene list. On the top of the list, FOXG1 expression is significantly (P < 0.0001) increased in the patient derived NPC samples. The differentially expressed gene list was highly overlapped with the SFARI autism gene set, identifying biological processes that are implicating neurological phenotype and ASD such as central nervous system development, neuron differentiation, and regulation of neurogenesis. The findings of the transcriptome deviation in early neuronal stage of MAND can provide potential connection to the overlapping neurocognitive and neuropsychiatric phenotypes associated with growing risk factors, such as other chromatin modifiers and epigenetic factors that link to ASD. Such in vitro models can nurture hypotheses toward therapeutic interventions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141835 | GEO | 2020/11/30

REPOSITORIES: GEO

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Project description:Autism spectrum disorder (ASD) is an early onset neurodevelopmental disorder, which is characterized by disturbances of brain function and behavioral deficits in core areas of impaired reciprocal socialization, impairment in communication skills, and repetitive or restrictive interests and behaviors. ASD is known to have a significant genetic risk, but the underlying genetic variation can be attributed to hundreds of genes. The molecular and pathophysiologic basis of ASD remains elusive because of its genetic heterogeneity and complexity, its high comorbidity with other diseases, and the paucity of brain tissue for study. The invasive nature of collecting primary neuronal tissue from patients might be circumvented through reprogramming peripheral cells to induced pluripotent stem cells (iPSCs), which are able to generate live neurons carrying the genetic variants of disease. This breakthrough allows us to access the cellular and molecular phenotypes of patients with âintrinsic autismâ, that is patients without known genetic disorders or identifiable syndromes or malformations. To do this, we studied a relatively homogeneous patient population of boys with intrinsic autism by excluding patients with known genetic disease or recognizable phenotypes or syndromes, as well as those with profound mental retardation or primary seizure disorders. We generated iPSCs from patients with intrinsic autism, their unaffected male siblings and age-, and sex-matched unaffected controls. And these stem cells were subsequently differentiated into electrophysiologically active neurons. The expression profile for autistic and their unaffected siblings' iPSC-derived neurons were compared. A distinct expression profile was found between autism and sib control. The significantly differentially expressed genes (> 2-fold, FDR < 0.05) in autistic iPSC-derived neurons were significantly enriched for processes related to synaptic transmission, such as neuroactive ligand-receptor signaling and extracellular matrix interactions (FDR < 0.05), and were significantly enriched for genes previously associated with ASD (p < 0.05). Our findings suggest approaches such as iPSC-derived neurons will be an important method to obtain tissue for study that appropriately recapitulates the complex dynamics of an autistic neural cell. We generated induced pluripotent stem cells (iPSCs) from male patients with intrinsic autism, their unaffected male siblings, and age-, and sex-matched unaffected controls. And these stem cells were subsequently differentiated into electrophysiologically active neurons following 80 days of post-mitotic neural differentiation. These samples, including fibroblast, iPSC, iPSC-derived neural progenitors (NPC) and iPSC-derived neurons, were analyzed for the change of gene expression profile by whole genome microarray.

Project description:Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder. To identify potential A2BP1-dependent differential splicing events in ASD brain, we performed high-throughput RNA sequencing (RNA-Seq) on three autism samples with significant downregulation of A2BP1 (average fold change by quantitative RT-PCR = 5.9) and three control samples with average A2BP1 levels. The list of potential A2BP1-depending differential splicing events in ASD is given in the Supplementary file linked at the foot of this record.

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Transcriptome deviation in early neuronal stage of MBD5-Associated Neurodevelopmental Disorder (MAND)

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