Methylmalonic aciduria cblB type: characterization of two novel mutations and mitochondrial dysfunction studies. (6th June 2014)

• Record Type: Journal Article
• Authors: Brasil, S.; Richard, E.; Jorge‐Finnigan, A.; Leal, F.; Merinero, B.; Banerjee, R.; Desviat, L.R.; Ugarte, M.; Pérez, B.
• Is Part Of: Clinical genetics. Volume 87:Number 6(2015:Jun.)
• Page Start: 576
• Page End: 581
• Publication Date: 2014-06-06
• Subjects: Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.12426
• Languages: English
• ISSNs: 0009-9163

Abstract

<abstract abstract-type="main" id="cge12426-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p id="cge12426-para-0001">Methylmalonic aciduria (MMA) <italic>cblB</italic> type is caused by mutations in the <italic>MMAB</italic> 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 <italic>cblB</italic> 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 <italic>cblB</italic> patients' fibroblasts. The recovery of mitochondrial function should be a goal in efforts to improve the clinical outcome of MMA <italic>cblB</italic> type.</p> </abstract>