Partial loss of CFIm25 causes learning deficits and aberrant neuronal alternative polyadenylation.

Abstract

We previously showed that <i>NUDT21</i>-spanning copy-number variations (CNVs) are associated with intellectual disability (Gennarino et al., 2015). However, the patients' CNVs also included other genes. To determine if reduced <i>NUDT21</i> function alone can cause disease, we generated <i>Nudt21</i>^+/- mice to mimic <i>NUDT21</i>-deletion patients. We found that although these mice have 50% reduced <i>Nudt21</i> mRNA, they only have 30% less of its cognate protein, CFIm25. Despite this partial protein-level compensation, the <i>Nudt21</i>^+/- mice have learning deficits, cortical hyperexcitability, and misregulated alternative polyadenylation (APA) in their hippocampi. Further, to determine the mediators driving neural dysfunction in humans, we partially inhibited <i>NUDT21</i> in human stem cell-derived neurons to reduce CFIm25 by 30%. This induced APA and protein level misregulation in hundreds of genes, a number of which cause intellectual disability when mutated. Altogether, these results show that disruption of <i>NUDT21</i>-regulated APA events in the brain can cause intellectual disability.