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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.
Afiliación
  • Wiedemann A; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France; National Center of Inborn Errors of Metabolism, University Regional Hospital Center of Nancy, Nancy, F-54000, France.
  • Oussalah A; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France; National Center of Inborn Errors of Metabolism, University Regional Hospital Center of Nancy, Nancy, F-54000, France.
  • Guéant Rodriguez RM; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France; National Center of Inborn Errors of Metabolism, University Regional Hospital Center of Nancy, Nancy, F-54000, France.
  • Jeannesson E; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France; National Center of Inborn Errors of Metabolism, University Regional Hospital Center of Nancy, Nancy, F-54000, France.
  • Mertens M; National Center of Inborn Errors of Metabolism, University Regional Hospital Center of Nancy, Nancy, F-54000, France.
  • Rotaru I; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France; National Center of Inborn Errors of Metabolism, University Regional Hospital Center of Nancy, Nancy, F-54000, France.
  • Alberto JM; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France.
  • Baspinar O; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France.
  • Rashka C; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France.
  • Hassan Z; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France.
  • Siblini Y; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France.
  • Matmat K; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France.
  • Jeandel M; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France.
  • Chery C; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France.
  • Robert A; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France.
  • Chevreux G; Université Paris Cité, CNRS, Institut Jacques Monod, F-75013, Paris, France.
  • Lignières L; Université Paris Cité, CNRS, Institut Jacques Monod, F-75013, Paris, France.
  • Camadro JM; Université Paris Cité, CNRS, Institut Jacques Monod, F-75013, Paris, France.
  • Feillet F; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France; National Center of Inborn Errors of Metabolism, University Regional Hospital Center of Nancy, Nancy, F-54000, France.
  • Coelho D; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France; National Center of Inborn Errors of Metabolism, University Regional Hospital Center of Nancy, Nancy, F-54000, France.
  • Guéant JL; Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, F-54000, France; National Center of Inborn Errors of Metabolism, University Regional Hospital Center of Nancy, Nancy, F-54000, France. Electronic address: jean-louis.gueant@univ-lorraine.fr.
EBioMedicine ; 99: 104911, 2024 Jan.
Article en En | MEDLINE | ID: mdl-38168585
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 CoA3-oxoacid CoA transferase deficiency), and MT-CO1 (cytochrome C oxidase subunit 1). Proteomic changes were observed for key mitochondrial enzymes, including NADHubiquinone 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Vitamina B 12 / Multiómica Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: EBioMedicine Año: 2024 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Vitamina B 12 / Multiómica Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: EBioMedicine Año: 2024 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Países Bajos