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1.
Clin Genet ; 87(6): 576-81, 2015 Jun.
Article in English | MEDLINE | ID: mdl-24813872

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.


Subject(s)
Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/metabolism , Mitochondria/genetics , Mitochondria/metabolism , Mutation , Alkyl and Aryl Transferases/genetics , Alkyl and Aryl Transferases/metabolism , Alleles , Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Substitution , Fibroblasts/metabolism , Humans , Intracellular Space/metabolism , Mitochondria/ultrastructure , Outcome Assessment, Health Care , Oxidative Stress/genetics , Reactive Oxygen Species/metabolism , Siblings
2.
Hum Mutat ; 30(12): 1676-82, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19862841

ABSTRACT

Development of pseudoexon exclusion therapies by antisense modification of pre-mRNA splicing represents a type of personalized genetic medicine. Here we present the cellular antisense therapy and the cell-based splicing assays to investigate the effect of two novel deep intronic changes c.1957-898A>G and c.1957-920C>A identified in the methylmalonyl-coenzyme A (CoA) mutase (MUT) gene. The results show that the nucleotide change c.1957-898A>G is a pathological mutation activating pseudoexon insertion and that antisense morpholino oligonucleotide (AMO) treatment in patient fibroblasts leads to recovery of MUT activity to levels 25 to 100% of control range. On the contrary, the change c.1957-920C>A, identified in two fibroblasts cell lines in cis with c.1885A>G (p.R629G) or c.458T>A (p.D153V), appears to be a rare variant of uncertain clinical significance. The functional analysis of c.1885A>G and c.458T>A indicate that they are the disease-causing mutations in these two patients. The results presented here highlight the necessity of scanning the described intronic region for mutations in MUT-affected patients, followed by functional analyses to demonstrate the pathogenicity of the identified changes, and extend previous work of the applicability of the antisense approach in methylmalonic aciduria (MMAuria) for a novel intronic mutation.


Subject(s)
Exons/genetics , Metabolism, Inborn Errors/drug therapy , Oligonucleotides, Antisense/therapeutic use , Base Sequence , Cell Line , Genotype , Humans , Introns/genetics , Metabolism, Inborn Errors/enzymology , Methylmalonyl-CoA Mutase/deficiency , Molecular Sequence Data , Mutation/genetics , Phenotype , Propionates/metabolism , RNA Splicing/genetics
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