title: Methylmalonic aciduria cblB type: characterization of two novel mutations and mitochondrial dysfunction studies.
abstract: Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene, which codes for the enzyme adenosine triphosphate (ATP): cobalamin adenosyltransferase (ATR). This study reports differences in the metabolic and disease outcomes of two pairs of siblings with MMA cblB type, respectively harbouring the novel changes p.His183Leu/p.Arg190dup (P1 and P2) and the previously described mutations p.Ile96Thr/p.Ser174fs (P3 and P4). Expression analysis showed p.His183Leu and p.Arg190dup to be destabilizing mutations. Both were associated with reduced ATR stability and a shorter half-life than wild-type ATR. Analysis of several parameters related to oxidative stress and mitochondrial function showed an increase in reactive oxygen species (ROS) content, a decrease in mitochondrial respiration and changes in mitochondria morphology and structure in patient-derived fibroblasts compared to control cells. The impairment in energy production and the presence of oxidative stress and fission of the mitochondrial reticulum suggested mitochondrial dysfunction in cblB patients' fibroblasts. The recovery of mitochondrial function should be a goal in efforts to improve the clinical outcome of MMA cblB type.
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Investigación Biomédica, IDIPaz, Madrid, Spain; Metabolism & Genetics Group, Research Institute for Medicines and Pharmaceuticals Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
authors.forename: S
authors.initials: S
authors.lastname: Brasil
authors.forename: E
authors.initials: E
authors.lastname: Richard
authors.forename: A
authors.initials: A
authors.lastname: Jorge-Finnigan
authors.forename: F
authors.initials: F
authors.lastname: Leal
authors.forename: B
authors.initials: B
authors.lastname: Merinero
authors.forename: R
authors.initials: R
authors.lastname: Banerjee
authors.forename: L R
authors.initials: LR
authors.lastname: Desviat
authors.forename: M
authors.initials: M
authors.lastname: Ugarte
authors.forename: B
authors.initials: B
authors.lastname: Pérez
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000378:metabolism; D000483:Alleles; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D019943:Amino Acid Substitution; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D017063:Outcome Assessment, Health Care; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D035781:Siblings
chemical_list: D017382:Reactive Oxygen Species; D019883:Alkyl and Aryl Transferases; C019920:cob(I)alamin adenosyltransferase
keywords: MMAB gene; methylmalonic aciduria; mitochondrial function; mutation