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| Status |
Public on Apr 06, 2023 |
| Title |
A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatial-temporal regulation of histone arginine methylation in neurodevelopment |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
We report a loss-of-function mutation in the TLDc domain of human Oxidation Resistance 1 (OXR1) gene, resulting in early-onset epilepsy, developmental delay, cognitive disabilities, and cerebellar atrophy. Patient lymphoblasts show impaired cell survival, proliferation, and hypersensitivity to oxidative stress. These phenotypes are rescued by TLDc domain replacement. We generated patient derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identified that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1 dependent mechanisms regulating gene expression during neurodevelopment. We modeled the function of OXR1 in early human brain development using patient derived brain organoids revealing that OXR1 contributes to the spatial-temporal regulation of histone arginine methylation in specific brain regions. Our work provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency, highlighting the therapeutic potential of OXR1 in numerous neurodegenerative and neurodevelopmental disorders.
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| Overall design |
We generated patient derived induced pluripotent stem cells (iPSCs) and performed neural differentiation assay. Three clones of control and the patient were used. The samples were collected at the stages of iPSCs, neural aggregates (NAs) and neurons(Neu), respectively.
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| Contributor(s) |
Lin X, Pannone M, Wang W, Yang M, Kristiansen E, Edvardson S, Ye J, Bjørås M |
| Citation missing |
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| Submission date |
Jun 21, 2022 |
| Last update date |
Jun 29, 2023 |
| Contact name |
Magnar Bjørås |
| E-mail(s) |
magnar.bjoras@ntnu.no
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| Organization name |
Faculty of Medicine and Health Sciences,NTNU
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| Department |
Department of Clinical and Molecular Medicine (IKOM)
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| Lab |
M.Bjørås´s Lab
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| Street address |
Erling Skjalgssonsgate 1
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| City |
Trondheim |
| ZIP/Postal code |
7030 |
| Country |
Norway |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA851462 |
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