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Updated: Nov 4, 2025
Rapid Detection of Neurodevelopmental Phenotypes in Human Neural Precursor Cells NPCs
Published on: March 2, 2018
Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals
Sureni V Mullegama1,2, Steven D Klein3,4,5, Stephen R Williams6
1Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
Abstract:
MBD5-associated neurodevelopmental disorder (MAND) is an autism spectrum disorder (ASD) characterized by intellectual disability, motor delay, speech impairment and behavioral problems; however, the biological role of methyl-CpG-binding domain 5, MBD5, in neurodevelopment and ASD remains largely undefined. Hence, we created neural progenitor cells (NPC) derived from individuals with chromosome 2q23.1 deletion and conducted RNA-seq to identify differentially expressed genes (DEGs) and the biological processes and pathways altered in MAND. Primary skin fibroblasts from three unrelated individuals with MAND and four unrelated controls were converted into induced pluripotent stem cell (iPSC) lines, followed by directed differentiation of iPSC to NPC. Transcriptome analysis of MAND NPC revealed 468 DEGs (q < 0.05), including 20 ASD-associated genes. Comparison of DEGs in MAND with SFARI syndromic autism genes revealed a striking significant overlap in biological processes commonly altered in neurodevelopmental phenotypes, with TGFβ, Hippo signaling, DNA replication, and cell cycle among the top enriched pathways. Overall, these transcriptome deviations provide potential connections to the overlapping neurocognitive and neuropsychiatric phenotypes associated with key high-risk ASD genes, including chromatin modifiers and epigenetic modulators, that play significant roles in these disease states.
Insights
Methyl-CpG-binding domain 5 (MBD5)-associated neurodevelopmental disorder (MAND) involves altered gene expression in neural progenitor cells. These changes highlight pathways crucial for neurodevelopment and autism spectrum disorder (ASD) phenotypes.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- MBD5-associated neurodevelopmental disorder (MAND) is an autism spectrum disorder (ASD) linked to chromosome 2q23.1 deletions.
- The precise biological role of MBD5 in neurodevelopment and ASD pathogenesis is not well understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying MAND by analyzing gene expression in neural progenitor cells (NPCs).
- To identify differentially expressed genes (DEGs) and altered biological pathways in MAND.
Main Methods:
- Induced pluripotent stem cells (iPSCs) were generated from MAND patient fibroblasts and differentiated into NPCs.
- RNA sequencing (RNA-seq) was performed on MAND NPCs and control NPCs to identify DEGs.
- DEGs were compared with known ASD-associated genes, including SFARI syndromic autism genes.
Main Results:
- Transcriptome analysis identified 468 DEGs in MAND NPCs (q < 0.05), including 20 genes associated with ASD.
- Significant overlap was observed between DEGs in MAND and biological processes altered in other neurodevelopmental phenotypes.
- Enriched pathways included TGFβ signaling, Hippo signaling, DNA replication, and cell cycle regulation.
Conclusions:
- Transcriptome deviations in MAND NPCs offer insights into the neurocognitive and neuropsychiatric features of the disorder.
- Findings suggest a connection between MBD5 dysfunction, epigenetic regulation, and ASD.
- Altered pathways may contribute to the complex phenotypes observed in MAND and other ASDs.
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