TY - JOUR
T1 - A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatial-temporal regulation of histone arginine methylation in neurodevelopment
AU - Lin, Xiaolin
AU - Wang, Wei
AU - Yang, Mingyi
AU - Damseh, Nadirah
AU - de Sousa, Mirta Mittelstedt Leal
AU - Jacob, Fadi
AU - Lång, Anna
AU - Kristiansen, Elise
AU - Pannone, Marco
AU - Kissova, Miroslava
AU - Almaas, Runar
AU - Kuśnierczyk, Anna
AU - Siller, Richard
AU - Shahrour, Maher
AU - Al-Ashhab, Motee
AU - Abu-Libdeh, Bassam
AU - Tang, Wannan
AU - Slupphaug, Geir
AU - Elpeleg, Orly
AU - Bøe, Stig Ove
AU - Eide, Lars
AU - Sullivan, Gareth J.
AU - Rinholm, Johanne Egge
AU - Song, Hongjun
AU - Ming, Guo-Li
AU - van Loon, Barbara
AU - Edvardson, Simon
AU - Ye, Jing
AU - Bjørås, Magnar
N1 - Funding was provided by the Research Council of Norway, South-East Norway Regional Health Authority and Central Region Norway Health Authority. The Proteomics and Metabolomics Core Facility PROMEC is funded by NTNU and the Central Norway Regional Health Authority and is a member of the National Network of Advanced Proteomics Infrastructure (NAPI), which is funded by the RCN INFRASTRUKTUR-program (295910).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - BackgroundOxidation 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.ResultsWe 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.ConclusionsThis study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients.
AB - BackgroundOxidation 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.ResultsWe 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.ConclusionsThis study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients.
KW - Oxidation Resistance 1 (OXR1)
KW - Induced pluripotent stem cells (iPSCs)
KW - Brain organoids
KW - Neurodevelopmental disorder
KW - Protein arginine methyltransferases (PRMTs)
KW - Histone arginine methylation
U2 - 10.1186/s13059-023-03037-1
DO - 10.1186/s13059-023-03037-1
M3 - Article
C2 - 37773136
SN - 1465-6906
VL - 24
JO - Genome Biology
JF - Genome Biology
IS - 1
M1 - 216
ER -
