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  1. Article ; Online: Correction: A transgenic mice model of retinopathy of cblG‑type inherited disorder of one‑carbon metabolism highlights epigenome‑wide alterations related to cone photoreceptor cells development and retinal metabolism.

    Matmat, Karim / Conart, Jean-Baptiste / Graindorge, Paul-Henri / El Kouche, Sandra / Hassan, Ziad / Siblini, Youssef / Umoret, Rémy / Safar, Ramia / Baspinar, Okan / Robert, Aurélie / Alberto, Jean-Marc / Oussalah, Abderrahim / Hergalant, Sébastien / Coelho, David / Guéant, Jean-Louis / Guéant-Rodriguez, Rosa-Maria

    Clinical epigenetics

    2024  Volume 16, Issue 1, Page(s) 23

    Language English
    Publishing date 2024-02-08
    Publishing country Germany
    Document type Published Erratum
    ZDB-ID 2553921-8
    ISSN 1868-7083 ; 1868-7075
    ISSN (online) 1868-7083
    ISSN 1868-7075
    DOI 10.1186/s13148-024-01636-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Multiomic analysis in fibroblasts of patients with inborn errors of cobalamin metabolism reveals concordance with clinical and metabolic variability.

    Wiedemann, Arnaud / Oussalah, Abderrahim / Guéant Rodriguez, Rosa-Maria / Jeannesson, Elise / Mertens, Marc / Rotaru, Irina / Alberto, Jean-Marc / Baspinar, Okan / Rashka, Charif / Hassan, Ziad / Siblini, Youssef / Matmat, Karim / Jeandel, Manon / Chery, Celine / Robert, Aurélie / Chevreux, Guillaume / Lignières, Laurent / Camadro, Jean-Michel / Feillet, François /
    Coelho, David / Guéant, Jean-Louis

    EBioMedicine

    2024  Volume 99, Page(s) 104911

    Abstract: Background: The high variability in clinical and metabolic presentations of inborn errors of cobalamin (cbl) metabolism (IECM), such as the cblC/epicblC types with combined deficits in methylmalonyl-coA mutase (MUT) and methionine synthase (MS), are not ...

    Abstract Background: The high variability in clinical and metabolic presentations of inborn errors of cobalamin (cbl) metabolism (IECM), such as the cblC/epicblC types with combined deficits in methylmalonyl-coA mutase (MUT) and methionine synthase (MS), are not well understood. They could be explained by the impaired expression/activity of enzymes from other metabolic pathways.
    Methods: We performed metabolomic, genomic, proteomic, and post-translational modification (PTM) analyses in fibroblasts from three cblC cases and one epi-cblC case compared with three cblG cases with specific MS deficits and control fibroblasts.
    Findings: CblC patients had metabolic profilings consistent with altered urea cycle, glycine, and energy mitochondrial metabolism. Metabolomic analysis showed partial disruption and increased glutamate/ketoglutarate anaplerotic pathway of the tricarboxylic acid cycle (TCA), in patient fibroblasts. RNA-seq analysis showed decreased expression of MT-TT (mitochondrial tRNA threonine), MT-TP (mitochondrial tRNA proline), OXCT1 (succinyl CoA:3-oxoacid CoA transferase deficiency), and MT-CO1 (cytochrome C oxidase subunit 1). Proteomic changes were observed for key mitochondrial enzymes, including NADH:ubiquinone oxidoreductase subunit A8 (NDUFA8), carnitine palmitoyltransferase 2 (CPT2), and ubiquinol-cytochrome C reductase, complex III subunit X (UQCR10). Propionaldehyde addition in ornithine aminotransferase was the predominant PTM in cblC cells and could be related with the dramatic cellular increase in propionate and methylglyoxalate. It is consistent with the decreased concentration of ornithine reported in 3 cblC cases. Whether the changes detected after multi-omic analyses underlies clinical features in cblC and cblG types of IECM, such as peripheral and central neuropathy, cardiomyopathy, pulmonary hypertension, development delay, remains to be investigated.
    Interpretation: The omics-related effects of IECM on other enzymes and metabolic pathways are consistent with the diversity and variability of their age-related metabolic and clinical manifestations. PTMs are expected to produce cumulative effects, which could explain the influence of age on neurological manifestations.
    Funding: French Agence Nationale de la Recherche (Projects PREDICTS and EpiGONE) and Inserm.
    MeSH term(s) Humans ; Vitamin B 12/metabolism ; Multiomics ; Proteomics ; Oxidoreductases/metabolism ; Fibroblasts/metabolism ; RNA, Transfer/metabolism
    Chemical Substances Vitamin B 12 (P6YC3EG204) ; Oxidoreductases (EC 1.-) ; RNA, Transfer (9014-25-9)
    Language English
    Publishing date 2024-01-01
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2851331-9
    ISSN 2352-3964
    ISSN (online) 2352-3964
    DOI 10.1016/j.ebiom.2023.104911
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A transgenic mice model of retinopathy of cblG-type inherited disorder of one-carbon metabolism highlights epigenome-wide alterations related to cone photoreceptor cells development and retinal metabolism.

    Matmat, Karim / Conart, Jean-Baptiste / Graindorge, Paul-Henri / El Kouche, Sandra / Hassan, Ziad / Siblini, Youssef / Umoret, Rémy / Safar, Ramia / Baspinar, Okan / Robert, Aurélie / Alberto, Jean-Marc / Oussalah, Abderrahim / Coelho, David / Guéant, Jean-Louis / Guéant-Rodriguez, Rosa-Maria

    Clinical epigenetics

    2023  Volume 15, Issue 1, Page(s) 158

    Abstract: Background: MTR gene encodes the cytoplasmic enzyme methionine synthase, which plays a pivotal role in the methionine cycle of one-carbon metabolism. This cycle holds a significant importance in generating S-adenosylmethionine (SAM) and S- ... ...

    Abstract Background: MTR gene encodes the cytoplasmic enzyme methionine synthase, which plays a pivotal role in the methionine cycle of one-carbon metabolism. This cycle holds a significant importance in generating S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), the respective universal methyl donor and end-product of epigenetic transmethylation reactions. cblG type of inherited disorders of vitamin B12 metabolism due to mutations in MTR gene exhibits a wide spectrum of symptoms, including a retinopathy unresponsive to conventional therapies.
    Methods: To unveil the underlying epigenetic pathological mechanisms, we conducted a comprehensive study of epigenomic-wide alterations of DNA methylation by NGS of bisulfited retinal DNA in an original murine model with conditional Mtr deletion in retinal tissue. Our focus was on postnatal day 21, a critical developmental juncture for ocular structure refinement and functional maturation.
    Results: We observed delayed eye opening and impaired visual acuity and alterations in the one-carbon metabolomic profile, with a notable dramatic decline in SAM/SAH ratio predicted to impair DNA methylation. This metabolic disruption led to epigenome-wide changes in genes involved in eye development, synaptic plasticity, and retinoid metabolism, including promoter hypermethylation of Rarα, a regulator of Lrat expression. Consistently, we observed a decline in cone photoreceptor cells and reduced expression of Lrat, Rpe65, and Rdh5, three pivotal genes of eye retinoid metabolism.
    Conclusion: We introduced an original in vivo model for studying cblG retinopathy, which highlighted the pivotal role of altered DNA methylation in eye development, cone differentiation, and retinoid metabolism. This model can be used for preclinical studies of novel therapeutic targets.
    MeSH term(s) Mice ; Animals ; Retinal Cone Photoreceptor Cells/metabolism ; Mice, Transgenic ; Epigenome ; DNA Methylation ; S-Adenosylmethionine/metabolism ; Retinal Diseases/metabolism ; Carbon/metabolism ; Retinoids/metabolism
    Chemical Substances S-Adenosylmethionine (7LP2MPO46S) ; Carbon (7440-44-0) ; Retinoids
    Language English
    Publishing date 2023-10-05
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553921-8
    ISSN 1868-7083 ; 1868-7075
    ISSN (online) 1868-7083
    ISSN 1868-7075
    DOI 10.1186/s13148-023-01567-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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