Trisomy 21 Drives ADARB1 Overexpression and Premature RNA Recoding in the Developing Fetal Brain

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Trisomy 21 (T21) causes Down syndrome, characterized by neurodevelopmental challenges.
• The precise mechanisms by which chromosome 21 gene dosage affects brain development are not fully understood.

Purpose of the Study:

• To investigate the impact of chromosome 21 gene dosage on gene expression and RNA editing in the developing fetal brain in T21.
• To identify specific genes and pathways dysregulated in T21 fetal brain tissue.

Main Methods:

• RNA sequencing of fetal cortical and hippocampal tissues from T21 cases and euploid controls.
• Analysis of gene expression dysregulation and pathway enrichment.
• Assessment of RNA editing levels, focusing on ADARB1 and its targets.

Main Results:

• Widespread gene expression dysregulation was observed in T21 fetal brains, with enrichment for chromosome 21 genes.
• ADARB1, a chromosome 21-encoded RNA editing enzyme, was significantly overexpressed in T21.
• Overexpression of ADARB1 correlated with increased adenosine-to-inosine RNA editing at critical sites in glutamate and GABA receptor genes.

Conclusions:

• Dysregulated RNA editing, driven by ADARB1 overexpression due to chromosome 21 gene dosage, is implicated as a post-transcriptional mechanism in T21 fetal neuropathology.
• These findings highlight RNA editing as a key factor in the neurodevelopmental outcomes associated with T21.