PXD014842

PXD014842 is an original dataset announced via ProteomeXchange.

Title	Partial loss of CFIm25 causes aberrant alternative polyadenylation and learning deficits
Description	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 NUDT21­-regulated APA events in the brain can cause intellectual disability.
HostingRepository	PRIDE
AnnounceDate	2020-04-27
AnnouncementXML	Submission_2020-04-26_23:35:41.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bhoomi Bhatt
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-31 01:23:19	ID requested
1	2019-08-01 02:47:11	announced
⏵ 2	2020-04-26 23:35:43	announced	2020-04-27: Updated publication reference for PubMed record(s): 32319885.

Alcott CE, Yalamanchili HK, Ji P, van der Heijden ME, Saltzman A, Elrod N, Lin A, Leng M, Bhatt B, Hao S, Wang Q, Saliba A, Tang J, Malovannaya A, Wagner EJ, Liu Z, Zoghbi HY, Partial loss of CFIm25 causes learning deficits and aberrant neuronal alternative polyadenylation. Elife, 9():(2020) [pubmed]

submitter keyword: Intellectual disability (ID), NUDT21, CFIm25, MeCP2, neurons

Huda Zoghbi
contact affiliation	Baylor College of Medicine, Houston, TX, 77054
contact email	hzoghbi@bcm.edu
lab head
Bhoomi Bhatt
contact affiliation	Baylor College of Medicine
contact email	bbhatt@bcm.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2019/08/PXD014842

PRIDE project URI

• PRIDE
  1. PXD014842
     1. Label: PRIDE project
     2. Name: Partial loss of CFIm25 causes aberrant alternative polyadenylation and learning deficits