Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Autism spectrum disorders (ASD) are complex neurodevelopmental conditions with numerous identified genetic risk loci, yet most cases remain idiopathic.
• Current genomic ASD research relies heavily on post-mortem brain tissue or cell lines, leaving early developmental transcriptional and regulatory processes incompletely understood.

Purpose of the Study:

• To investigate early developmental disturbances in ASD by analyzing stem cells from the nasal cavity.
• To identify novel genetic or regulatory factors contributing to ASD pathogenesis.

Main Methods:

• Isolation and comparison of stem cells from the nasal cavities of individuals with ASD and neurotypical controls.
• Analysis of gene expression, specifically focusing on the MOCOS gene and its associated noncoding RNA, COSMOC.
• Functional studies including knockdown experiments to assess the impact of COSMOC on gene expression and cellular processes.

Main Results:

• Discovery of COSMOC, an antisense long noncoding RNA, which is underexpressed in most ASD patients' stem cells.
• Loss of COSMOC leads to reduced MOCOS expression, disrupting redox homeostasis and synaptogenesis.
• COSMOC deficiency destabilizes cellular lipid and energy metabolism, impairs neuronal maturation, and affects synaptic gene splicing.

Conclusions:

• The underexpression of the COSMOC/MOCOS bidirectional unit in ASD may offer new perspectives on the disorder's origins.
• These findings highlight the potential role of noncoding RNAs in ASD pathogenesis and suggest avenues for future translational research.