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Loss-of-function mutation in human Oxidation Resistance gene 1 disrupts the spatial-temporal regulation of histone arginine methylation in early brain development

Xiaolin Lin, Wei Wang, Mingyi Yang, Nadirah Damseh, Mirta Mittelstedt Leal de Sousa, Fadi Jacob, Anna Lång, Elise Kristiansen, Marco Pannone, Miroslava Kissova, Runar Almaas, Anna Kuśnierczyk, Richard Siller, Maher Shahrour, Motee Al-Ashhab, Bassam Abu-Libdeh, Wannan Tang, Geir Slupphaug, Orly Elpeleg, Stig Ove Bøe, Lars Eide, Gareth J Sullivan, Johanne Egge Rinholm, Hongjun Song, Guo-li Ming, Barbara van Loon, Simon Edvardson, Jing Ye, Magnar Bjørås
doi: https://doi.org/10.1101/2022.05.24.493324
Xiaolin Lin
1Department of Microbiology, Oslo University Hospital and University of Oslo, Norway
2Department of Biochemistry, Oslo University Hospital and University of Oslo, Norway
9Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway
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Wei Wang
9Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway
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Mingyi Yang
1Department of Microbiology, Oslo University Hospital and University of Oslo, Norway
2Department of Biochemistry, Oslo University Hospital and University of Oslo, Norway
5Norwegian Centre for Stem Cell Research, Oslo University Hospital and University of Oslo, Norway
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Nadirah Damseh
7Department of Pediatrics, Makassed Hospital and Al-Quds University, East Jerusalem, Palestine
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Mirta Mittelstedt Leal de Sousa
9Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway
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Fadi Jacob
12Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA
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Anna Lång
1Department of Microbiology, Oslo University Hospital and University of Oslo, Norway
2Department of Biochemistry, Oslo University Hospital and University of Oslo, Norway
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Elise Kristiansen
1Department of Microbiology, Oslo University Hospital and University of Oslo, Norway
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Marco Pannone
9Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway
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Miroslava Kissova
9Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway
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Runar Almaas
13Department of Pediatric Research, Oslo University Hospital and University of Oslo, Norway
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Anna Kuśnierczyk
1Department of Microbiology, Oslo University Hospital and University of Oslo, Norway
10The Proteomics and Metabolomics Core Facility (PROMEC), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway
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Richard Siller
5Norwegian Centre for Stem Cell Research, Oslo University Hospital and University of Oslo, Norway
6Department of Molecular Medicine, University of Oslo, Norway
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Maher Shahrour
7Department of Pediatrics, Makassed Hospital and Al-Quds University, East Jerusalem, Palestine
14Department of Newborn and Developmental Paediatrics, Toronto, Ontario, Canada
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Motee Al-Ashhab
7Department of Pediatrics, Makassed Hospital and Al-Quds University, East Jerusalem, Palestine
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Bassam Abu-Libdeh
7Department of Pediatrics, Makassed Hospital and Al-Quds University, East Jerusalem, Palestine
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Wannan Tang
9Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway
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Geir Slupphaug
1Department of Microbiology, Oslo University Hospital and University of Oslo, Norway
10The Proteomics and Metabolomics Core Facility (PROMEC), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway
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Orly Elpeleg
15Department of Genetics, Hadassah University Hospital, Jerusalem, Israel
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Stig Ove Bøe
1Department of Microbiology, Oslo University Hospital and University of Oslo, Norway
2Department of Biochemistry, Oslo University Hospital and University of Oslo, Norway
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Lars Eide
2Department of Biochemistry, Oslo University Hospital and University of Oslo, Norway
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Gareth J Sullivan
3Department of Immunology, Oslo University Hospital and University of Oslo, Norway
5Norwegian Centre for Stem Cell Research, Oslo University Hospital and University of Oslo, Norway
6Department of Molecular Medicine, University of Oslo, Norway
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Johanne Egge Rinholm
1Department of Microbiology, Oslo University Hospital and University of Oslo, Norway
10The Proteomics and Metabolomics Core Facility (PROMEC), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway
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Hongjun Song
12Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA
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Guo-li Ming
12Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA
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Barbara van Loon
9Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway
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Simon Edvardson
15Department of Genetics, Hadassah University Hospital, Jerusalem, Israel
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  • For correspondence: Magnar.Bjoras@ntnu.no jing.ye@ntnu.no SIMON@hadassah.org.il
Jing Ye
9Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway
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  • For correspondence: Magnar.Bjoras@ntnu.no jing.ye@ntnu.no SIMON@hadassah.org.il
Magnar Bjørås
1Department of Microbiology, Oslo University Hospital and University of Oslo, Norway
2Department of Biochemistry, Oslo University Hospital and University of Oslo, Norway
5Norwegian Centre for Stem Cell Research, Oslo University Hospital and University of Oslo, Norway
9Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway
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  • For correspondence: Magnar.Bjoras@ntnu.no jing.ye@ntnu.no SIMON@hadassah.org.il
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Abstract

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.

Competing Interest Statement

The authors have declared no competing interest.

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Loss-of-function mutation in human Oxidation Resistance gene 1 disrupts the spatial-temporal regulation of histone arginine methylation in early brain development
Xiaolin Lin, Wei Wang, Mingyi Yang, Nadirah Damseh, Mirta Mittelstedt Leal de Sousa, Fadi Jacob, Anna Lång, Elise Kristiansen, Marco Pannone, Miroslava Kissova, Runar Almaas, Anna Kuśnierczyk, Richard Siller, Maher Shahrour, Motee Al-Ashhab, Bassam Abu-Libdeh, Wannan Tang, Geir Slupphaug, Orly Elpeleg, Stig Ove Bøe, Lars Eide, Gareth J Sullivan, Johanne Egge Rinholm, Hongjun Song, Guo-li Ming, Barbara van Loon, Simon Edvardson, Jing Ye, Magnar Bjørås
bioRxiv 2022.05.24.493324; doi: https://doi.org/10.1101/2022.05.24.493324
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Loss-of-function mutation in human Oxidation Resistance gene 1 disrupts the spatial-temporal regulation of histone arginine methylation in early brain development
Xiaolin Lin, Wei Wang, Mingyi Yang, Nadirah Damseh, Mirta Mittelstedt Leal de Sousa, Fadi Jacob, Anna Lång, Elise Kristiansen, Marco Pannone, Miroslava Kissova, Runar Almaas, Anna Kuśnierczyk, Richard Siller, Maher Shahrour, Motee Al-Ashhab, Bassam Abu-Libdeh, Wannan Tang, Geir Slupphaug, Orly Elpeleg, Stig Ove Bøe, Lars Eide, Gareth J Sullivan, Johanne Egge Rinholm, Hongjun Song, Guo-li Ming, Barbara van Loon, Simon Edvardson, Jing Ye, Magnar Bjørås
bioRxiv 2022.05.24.493324; doi: https://doi.org/10.1101/2022.05.24.493324

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