A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatial-temporal regulation of histone arginine methylation in neurodevelopment.

Autor:	Lin X; Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.; Department of Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway.; Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway.; Centre for Embryology and Healthy Development, University of Oslo and Oslo University Hospital, 0373, Oslo, Norway., Wang W; Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway., Yang M; Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.; Department of Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway.; Centre for Embryology and Healthy Development, University of Oslo and Oslo University Hospital, 0373, Oslo, Norway.; Norwegian Centre for Stem Cell Research, Oslo University Hospital and University of Oslo, Oslo, Norway., Damseh N; Department of Pediatrics, Makassed Hospital and Al-Quds University, East Jerusalem, Palestine., de Sousa MML; Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway., Jacob F; Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA, 19104, USA., Lång A; Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.; Department of Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway., Kristiansen E; Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.; Centre for Embryology and Healthy Development, University of Oslo and Oslo University Hospital, 0373, Oslo, Norway., Pannone M; Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway., Kissova M; Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway., Almaas R; Department of Pediatric Research, Oslo University Hospital and University of Oslo, Oslo, Norway., Kuśnierczyk A; Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.; The Proteomics and Metabolomics Core Facility (PROMEC), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway., Siller R; Norwegian Centre for Stem Cell Research, Oslo University Hospital and University of Oslo, Oslo, Norway.; Department of Molecular Medicine, University of Oslo, Oslo, Norway., Shahrour M; Department of Pediatrics, Makassed Hospital and Al-Quds University, East Jerusalem, Palestine.; Department of Newborn and Developmental Paediatrics, Toronto, ON, Canada., Al-Ashhab M; Department of Pediatrics, Makassed Hospital and Al-Quds University, East Jerusalem, Palestine., Abu-Libdeh B; Department of Pediatrics, Makassed Hospital and Al-Quds University, East Jerusalem, Palestine., Tang W; Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway., Slupphaug G; Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.; The Proteomics and Metabolomics Core Facility (PROMEC), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway., Elpeleg O; Department of Genetics, Hadassah University Hospital, Jerusalem, Israel., Bøe SO; Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.; Department of Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway., Eide L; Department of Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway., Sullivan GJ; Norwegian Centre for Stem Cell Research, Oslo University Hospital and University of Oslo, Oslo, Norway.; Department of Molecular Medicine, University of Oslo, Oslo, Norway.; Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway., Rinholm JE; Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.; The Proteomics and Metabolomics Core Facility (PROMEC), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway., Song H; Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA, 19104, USA., Ming GL; Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA, 19104, USA., van Loon B; Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway., Edvardson S; Department of Genetics, Hadassah University Hospital, Jerusalem, Israel. SIMON@hadassah.org.il., Ye J; Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway. jing.ye@ntnu.no., Bjørås M; Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway. Magnar.Bjoras@ntnu.no.; Department of Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway. Magnar.Bjoras@ntnu.no.; Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology (NTNU), 7491, Trondheim, Norway. Magnar.Bjoras@ntnu.no.; Centre for Embryology and Healthy Development, University of Oslo and Oslo University Hospital, 0373, Oslo, Norway. Magnar.Bjoras@ntnu.no.; Norwegian Centre for Stem Cell Research, Oslo University Hospital and University of Oslo, Oslo, Norway. Magnar.Bjoras@ntnu.no.
Jazyk:	angličtina
Zdroj:	Genome biology [Genome Biol] 2023 Sep 29; Vol. 24 (1), pp. 216. Date of Electronic Publication: 2023 Sep 29.
DOI:	10.1186/s13059-023-03037-1
Abstrakt:	Background: Oxidation Resistance 1 (OXR1) gene is a highly conserved gene of the TLDc domain-containing family. OXR1 is involved in fundamental biological and cellular processes, including DNA damage response, antioxidant pathways, cell cycle, neuronal protection, and arginine methylation. In 2019, five patients from three families carrying four biallelic loss-of-function variants in OXR1 were reported to be associated with cerebellar atrophy. However, the impact of OXR1 on cellular functions and molecular mechanisms in the human brain is largely unknown. Notably, no human disease models are available to explore the pathological impact of OXR1 deficiency. Results: We report a novel loss-of-function mutation in the TLDc domain of the human 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 generate patient-derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identify that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1-dependent mechanisms regulating gene expression during neurodevelopment. We model 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. Conclusions: This study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients. (© 2023. BioMed Central Ltd., part of Springer Nature.)
Databáze:	MEDLINE
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