TY - JOUR
T1 - Partial loss of CFIM25 causes learning deficits and aberrant neuronal alternative polyadenylation
AU - Alcott, Callison E.
AU - Yalamanchili, Hari Krishna
AU - Ji, Ping
AU - van der Heijden, Meike E.
AU - Saltzman, Alexander
AU - Elrod, Nathan
AU - Lin, Ai
AU - Leng, Mei
AU - Bhatt, Bhoomi
AU - Hao, Shuang
AU - Wang, Qi
AU - Saliba, Afaf
AU - Tang, Jianrong
AU - Malovannaya, Anna
AU - Wagner, Eric J.
AU - Liu, Zhandong
AU - Zoghbi, Huda Y.
N1 - Funding Information:
We would like to thank the Zoghbi and Wagner lab members for critical feedback. We would also like to thank the cores that provided services for the project: the Microscopy, Neuroconnectivity, Animal Behavior, and Human Neuronal Differentiation cores from the Jan and Dan Duncan Neurological Research Institute and BCM Intellectual and Developmental Disabilities Research Center (NIH U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development); the Next Generation Sequencing core at the University of Texas Medical Branch; and BCM Mass Spectrometry Core (supported by NIH P30 CA125123 and CPRIT RP170005). Lastly, we would like to thank our funders who made the work possible: the NIH National Institute of Neurological Disorders and Stroke—F30NS095449 (CEA), National Cancer Institute—R03-CA223893-01 (PJ), National Institute of General Medical Sciences—R01-GM134539 (EJW), the Howard Hughes Medical Institute (HYZ), and the Intellectual and Developmental Disabilities Research Center—NIH U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HYZ). The content is solely the responsibility of the authors and does not represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, or the Howard Hughes Medical Institute.
Publisher Copyright:
© Alcott et al.
PY - 2020/4
Y1 - 2020/4
N2 - We previously showed that NUDT21-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 NUDT21 function alone can cause disease, we generated Nudt21+/- mice to mimic NUDT21-deletion patients. 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, cortical hyperexcitability, and misregulated alternative polyadenylation (APA) in their hippocampi. Further, to determine the mediators driving neural dysfunction in humans, we partially inhibited NUDT21 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 NUDT21-regulated APA events in the brain can cause intellectual disability.
AB - We previously showed that NUDT21-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 NUDT21 function alone can cause disease, we generated Nudt21+/- mice to mimic NUDT21-deletion patients. 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, cortical hyperexcitability, and misregulated alternative polyadenylation (APA) in their hippocampi. Further, to determine the mediators driving neural dysfunction in humans, we partially inhibited NUDT21 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 NUDT21-regulated APA events in the brain can cause intellectual disability.
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U2 - 10.7554/eLife.50895
DO - 10.7554/eLife.50895
M3 - Article
C2 - 32319885
AN - SCOPUS:85084025111
SN - 2050-084X
VL - 9
JO - eLife
JF - eLife
M1 - e50895
ER -