Partial loss of CFIm25 causes aberrant alternative polyadenylation and learning deficits
Callison E. Alcott,
Hari Krishna Yalamanchili,
Meike E. van der Heijden,
Alexander B. Saltzman,
Eric J Wagner,
Huda Y. Zoghbi
Posted 14 Aug 2019
bioRxiv DOI: 10.1101/735597
Posted 14 Aug 2019
We previously showed that NUDT21 -spanning copy-number variations (CNVs) are associated with intellectual disability (ID) (Gennarino et al., 2015). However, the patients' CNVs also spanned multiple other genes. To determine if reduced NUDT21 function alone is sufficient to cause disease, we generated Nudt21 +/- mice to mimic the human state of reduced expression. We found that although these mice have 50% reduced Nudt21 mRNA, they only have 30% less of its cognate protein, CFIm25. Despite this partial protein-level compensation, the Nudt21 +/- mice have learning deficits and cortical hyperexcitability. Further, to determine the molecular mechanism driving neural dysfunction, we partially inhibited NUDT21 in human embryonic stem cell-derived neurons to reduce CFIm25 by 30%. This reduction in CFIm25 was sufficient to induce misregulated alternative polyadenylation (APA) and protein levels in hundreds of genes, dozens of which cause intellectual disability when mutated. Altogether, these results indicate that disruption of NUDT21 -regulated APA events in the brain can cause intellectual disability.
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