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

We previously showed that -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 function alone can cause disease, we generated mice to mimic -deletion patients. We found that although these mice have 50% reduced mRNA, they only have 30% less of its cognate protein, CFIm25. Despite this partial protein-level compensation, the 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 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 -regulated APA events in the brain can cause intellectual disability.