Multiomic Analysis in Fibroblasts of Patients with Inborn Errors of Cobalamin Metabolism Reveals Concordance with Clinical and Metabolic Variability

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2024 Jan 3

PMID 38168585

Authors

Arnaud Wiedemann

Abderrahim Oussalah

Rosa-Maria Gueant Rodriguez

Elise Jeannesson

Marc Mertens

Marc Merten

Irina Rotaru

Jean-Marc Alberto

Okan Baspinar

Charif Rashka

Ziad Hassan

Youssef Siblini

Karim Matmat

Manon Jeandel

Celine Chery

Aurelie Robert

Guillaume Chevreux

Laurent Lignieres

Jean-Michel Camadro

Sebastien Hergalant

Francois Feillet

David Coelho

Jean-Louis Gueant

Affiliations

Soon will be listed here.

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.

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