title: Different altered pattern expression of genes related to apoptosis in isolated methylmalonic aciduria cblB type and combined with homocystinuria cblC type.
abstract: An increased reactive oxygen species (ROS) production and apoptosis rate have been associated with several disorders involved in cobalamin metabolism, including isolated methylmalonic aciduria (MMA) cblB type and MMA combined with homocystinuria (MMAHC) cblC type. Given the relevance of p38 and JNK kinases in stress-response, their activation in fibroblasts from a spectrum of patients (mut, cblA, cblB, cblC and cblE) was analyzed revealing an increased expression of the phosphorylated-forms, specially in cblB and cblC cell lines that presented the highest ROS and apoptosis levels. To gain further insight into the molecular mechanisms responsible for the enhanced apoptotic process observed in cblB and cblC fibroblasts, we evaluated the expression pattern of 84 apoptosis-related genes by quantitative real-time PCR. An elevated number of pro-apoptotic genes were overexpressed in cblC cells showing a higher rate of apoptosis compared to cblB and control samples. Additionally, apoptosis appears to be mainly triggered through the extrinsic pathway in cblC, while the intrinsic pathway was primarily activated in cblB cells. The differences observed regarding the apoptosis rate and preferred pathway between cblB and cblC patients, who both built up methylmalonic acid, might be explained by the accumulated homocysteine in the cblC group. The loss of MMACHC function in cblC patients might be partially responsible for the oxidative stress and apoptosis processes observed in these cell lines. Our results suggest that ROS production may represent a genetic modifier of the phenotype and support the potential of using antioxidants as a novel therapeutic strategy to improve the severe neurological outcome of these rare diseases.
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, Centro De Biología Molecular Severo Ochoa, CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de madrid, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Jorge-Finnigan
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gámez
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ugarte
authors.forename: Eva
authors.initials: E
authors.lastname: Richard
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D006712:Homocystinuria / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008764:Methylmalonic Acid / Q000378:metabolism; D009154:Mutation; D010088:Oxidoreductases; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D008764:Methylmalonic Acid; C508359:MMACHC protein, human; D010088:Oxidoreductases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases