Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures

Paramasivam, Arumugam; Meena, A K; Venkatapathi, Challa; Pitceathly, Robert D S; Thangaraj, Kumarasamy

doi:10.1007/s12031-020-01595-8

Cited by 28 publications

(27 citation statements)

References 11 publications

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“…Thus, f 5 C formation is disturbed by mutations in either ALKBH1 or NSUN3. Patients with NSUN3 mutations show a combined developmental disability and microcephaly [28,29]. These symptoms were not completely consistent with the phenotype observed in our established Alkbh1 KO mice.…”

Section: Discussioncontrasting

confidence: 50%

Telencephalon‐specific Alkbh1 conditional knockout mice display hippocampal atrophy and impaired learning

et al. 2021

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AlkB homolog 1 (ALKBH1) is responsible for the biogenesis of 5-formylcytidine (f 5 C) on mitochondrial tRNA Met and essential for mitochondrial protein synthesis. The brain, especially the hippocampus, is highly susceptible to mitochondrial dysfunction; hence, the maintenance of mitochondrial activity is strongly required to prevent disorders associated with hippocampal malfunction. To study the role of ALKBH1 in the hippocampus, we generated dorsal telencephalon-specific Alkbh1 conditional knockout (cKO) mice in inbred C57BL/6 background. These mice showed reduced activity of the respiratory chain complex, hippocampal atrophy, and CA1 pyramidal neuron abnormalities. Furthermore, performances in the fearconditioning and Morris water maze tests in cKO mice indicated that the hippocampal abnormalities led to impaired hippocampus-dependent learning. These findings indicate critical roles of ALKBH1 in the hippocampus.

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Section: Discussioncontrasting

confidence: 50%

Telencephalon‐specific Alkbh1 conditional knockout mice display hippocampal atrophy and impaired learning

et al. 2021

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“…The reason may be that advanced tumors require a lot of energy and tumor cells improve their mitochondrial activity and obtain more energy by self-upregulating NSUN4 and other genes. NSUN3 was a putative methyltransferase in mitochondria [28], whose aberration may lead to a variety of diseases [29,30]. Many studies have reported that TET2 can inhibit tumors, and its mutation can induce the occurrence and development of tumors [31][32][33][34].…”

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confidence: 99%

Comprehensive Analysis of m5C RNA Methylation Regulator Genes in Clear Cell Renal Cell Carcinoma

Hou

Wang

et al. 2021

International Journal of Genomics

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Background. Recent research found that N5-methylcytosine (m5C) was involved in the development and occurrence of numerous cancers. However, the function and mechanism of m5C RNA methylation regulators in clear cell renal cell carcinoma (ccRCC) remains undiscovered. This study is aimed at investigating the predictive and clinical value of these m5C-related genes in ccRCC. Methods. Based on The Cancer Genome Atlas (TCGA) database, the expression patterns of twelve m5C regulators and matched clinicopathological characteristics were downloaded and analyzed. To reveal the relationships between the expression levels of m5C-related genes and the prognosis value in ccRCC, consensus clustering analysis was carried out. By univariate Cox analysis and last absolute shrinkage and selection operator (LASSO) Cox regression algorithm, a m5C-related risk signature was constructed in the training group and further validated in the testing group and the entire cohort. Then, the predictive ability of survival of this m5C-related risk signature was analyzed by Cox regression analysis and nomogram. Functional annotation and single-sample Gene Set Enrichment Analysis (ssGSEA) were applied to further explore the biological function and potential signaling pathways. Furthermore, we performed qRT-PCR experiments and measured global m5C RNA methylation level to validate this signature in vitro and tissue samples. Results. In the TCGA-KIRC cohort, we found significant differences in the expression of m5C RNA methylation-related genes between ccRCC tissues and normal kidney tissues. Consensus cluster analysis was conducted to separate patients into two m5C RNA methylation subtypes. Significantly better outcomes were observed in ccRCC patients in cluster 1 than in cluster 2. m5C RNA methylation-related risk score was calculated to evaluate the prognosis of ccRCC patients by seven screened m5C RNA methylation regulators (NOP2, NSUN2, NSUN3, NSUN4, NSUN5, TET2, and DNMT3B) in the training cohort. The AUC for the 1-, 2-, and 3-year survival in the training cohort were 0.792, 0.675, and 0.709, respectively, indicating that the risk signature had an excellent prognosis prediction in ccRCC. Additionally, univariate and multivariate Cox regression analyses revealed that the risk signature could be an independent prognostic factor in ccRCC. The results of ssGSEA suggested that the immune cells with different infiltration degrees between the high-risk and low-risk groups were T cells including follicular helper T cells, Th1_cells, Th2_cells, and CD8+_T_cells, and the main differences in immune-related functions between the two groups were the interferon response and T cell costimulation. In addition, qRT-PCR experiments confirmed our results in renal cell lines and tissue samples. Conclusions. According to the seven selected regulatory factors of m5C RNA methylation, a risk signature associated with m5C methylation that can independently predict prognosis in patients with ccRCC was developed and further verified the predictive efficiency.

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“…Diseases related to energy metabolism disorder are also associated with the mitochondrial RNA m 5 C modification. For example, NSUN3 may be associated with multisystem mitochondrial disease associated with a combined oxidative phosphorylation deficiency 108 . In leukemia cells, NSUN3/DNMT2 and NSUN1 regulate the formation of 5-azacitidine-sensitive chromatin structures in an antagonistic manners 25 .…”

Section: Biological Function Of M 5 C In Eukaryote and Diseasementioning

confidence: 99%

The role of RNA m⁵C modification in cancer metastasis

et al. 2021

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Epigenetic modification plays a crucial regulatory role in the biological processes of eukaryotic cells. The recent characterization of DNA and RNA methylation is still ongoing. Tumor metastasis has long been an unconquerable feature in the fight against cancer. As an inevitable component of the epigenetic regulatory network, 5-methylcytosine is associated with multifarious cellular processes and systemic diseases, including cell migration and cancer metastasis. Recently, gratifying progress has been achieved in determining the molecular interactions between m 5 C writers (DNMTs and NSUNs), demethylases (TETs), readers (YTHDF2, ALYREF and YBX1) and RNAs. However, the underlying mechanism of RNA m 5 C methylation in cell mobility and metastasis remains unclear. The functions of m 5 C writers and readers are believed to regulate gene expression at the post-transcription level and are involved in cellular metabolism and movement. In this review, we emphatically summarize the recent updates on m 5 C components and related regulatory networks. The content will be focused on writers and readers of the RNA m 5 C modification and potential mechanisms in diseases. We will discuss relevant upstream and downstream interacting molecules and their associations with cell migration and metastasis.

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Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures

Cited by 28 publications

References 11 publications

Telencephalon‐specific Alkbh1 conditional knockout mice display hippocampal atrophy and impaired learning

Telencephalon‐specific Alkbh1 conditional knockout mice display hippocampal atrophy and impaired learning

Comprehensive Analysis of m5C RNA Methylation Regulator Genes in Clear Cell Renal Cell Carcinoma

The role of RNA m⁵C modification in cancer metastasis

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Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial Encephalomyopathy and Seizures

Cited by 28 publications

References 11 publications

Telencephalon‐specific Alkbh1 conditional knockout mice display hippocampal atrophy and impaired learning

Telencephalon‐specific Alkbh1 conditional knockout mice display hippocampal atrophy and impaired learning

Comprehensive Analysis of m5C RNA Methylation Regulator Genes in Clear Cell Renal Cell Carcinoma

The role of RNA m5C modification in cancer metastasis

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The role of RNA m⁵C modification in cancer metastasis