Program in Developmental Biology, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Medical Scientist Training Program, Baylor College of Medicine, Houston, United States
Hari Krishna Yalamanchili
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
Ping Ji
Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, United States
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Department of Neuroscience, Baylor College of Medicine, Houston, United States
Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, United States
Ai Lin
Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, United States; Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Mei Leng
Verna and Marrs McLean Department of Biochemistry and Molecular Biology Baylor College of Medicine, Houston, United States
Bhoomi Bhatt
Verna and Marrs McLean Department of Biochemistry and Molecular Biology Baylor College of Medicine, Houston, United States
Shuang Hao
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Section of Neurology, Department of Pediatrics, Baylor College of Medicine, Houston, United States
Qi Wang
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Section of Neurology, Department of Pediatrics, Baylor College of Medicine, Houston, United States
Afaf Saliba
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
Jianrong Tang
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Section of Neurology, Department of Pediatrics, Baylor College of Medicine, Houston, United States
Anna Malovannaya
Verna and Marrs McLean Department of Biochemistry and Molecular Biology Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States
Eric J Wagner
Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston, United States
Zhandong Liu
Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Section of Neurology, Department of Pediatrics, Baylor College of Medicine, Houston, United States; Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, United States
Program in Developmental Biology, Baylor College of Medicine, Houston, United States; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Department of Neuroscience, Baylor College of Medicine, Houston, United States; Department of Pediatrics, Baylor College of Medicine, Houston, United States; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States
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.