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| Status |
Public on Apr 15, 2020 |
| Title |
Partial loss of CFIm25 causes aberrant alternative polyadenylation and learning deficits [human] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
We previously showed that NUDT21-spanning copy-number variations (CNVs) are associated with intellectual disability (ID), and that NUDT21-encoded CFIm25 regulates the protein levels of at least one dose-sensitive, ID-associated protein: MeCP2 (Gennarino et al., 2015). However, the patients’ CNVs also spanned multiple other genes raising the possibility that loss or gain of these other genes caused their symptoms. To determine if reduced NUDT21 function alone is sufficient to cause disease, we generated Nudt21 heterozygous null 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 are associated with intellectual disability and whose dysregulation is likely contributing to disease symptoms. Altogether, these results indicate that disruption of NUDT21Â-regulated APA events in the brain can cause intellectual disability.
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| Overall design |
Anti-NUDT21 and scramble shRNA-infected WA09 human embryonic stem cell-derived excitatory neuron mRNA 3' end sequencing profiles generated by deep sequencing, in triplicate, using Illumina Nextseq 550.
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| Contributor(s) |
Alcott CE, Yalamanchili HK, Ji P, van der Heijden ME, Saltzman AB, Elrod N, Leng M, Bhatt B, Hao S, Wang Q, Saliba A, Tang J, Malovannaya A, Wagner EJ, Liu Z, Zoghbi HY |
| Citation(s) |
32319885 |
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| Submission date |
Dec 27, 2019 |
| Last update date |
Apr 27, 2020 |
| Contact name |
Hari Krishna Yalamanchili |
| E-mail(s) |
[email protected]
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| Organization name |
Baylor College of Medicine
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| Street address |
1250 Moursund St #1125,
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| City |
Houston, |
| State/province |
TX |
| ZIP/Postal code |
77030 |
| Country |
USA |
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| Platforms (1) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE142683 |
Partial loss of CFIm25 causes aberrant alternative polyadenylation and learning deficits [superseries] |
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| Relations |
| BioProject |
PRJNA597919 |
| SRA |
SRP238933 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE142682_RAW.tar |
247.8 Mb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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