title: A novel regulatory defect in the branched-chain α-keto acid dehydrogenase complex due to a mutation in the PPM1K gene causes a mild variant phenotype of maple syrup urine disease.
abstract: This article describes a hitherto unreported involvement of the phosphatase PP2Cm, a recently described member of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, in maple syrup urine disease (MSUD). The disease-causing mutation was identified in a patient with a mild variant phenotype, involving a gene not previously associated with MSUD. SNP array-based genotyping showed a copy-neutral homozygous pattern for chromosome 4 compatible with uniparental isodisomy. Mutation analysis of the candidate gene, PPM1K, revealed a homozygous c.417_418delTA change predicted to result in a truncated, unstable protein. No PP2Cm mutant protein was detected in immunocytochemical or Western blot expression analyses. The transient expression of wild-type PPM1K in PP2Cm-deficient fibroblasts recovered 35% of normal BCKDH activity. As PP2Cm has been described essential for cell survival, apoptosis and metabolism, the impact of its deficiency on specific metabolic stress variables was evaluated in PP2Cm-deficient fibroblasts. Increases were seen in ROS levels along with the activation of specific stress-signaling MAP kinases. Similar to that described for the pyruvate dehydrogenase complex, a defect in the regulation of BCKDH caused the aberrant metabolism of its substrate, contributing to the patient's MSUD phenotype--and perhaps others.
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, CIBERER U746, IDIPAZ, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Oyarzabal
authors.forename: Mercedes
authors.initials: M
authors.lastname: Martínez-Pardo
authors.forename: Begoña
authors.initials: B
authors.lastname: Merinero
authors.forename: Rosa
authors.initials: R
authors.lastname: Navarrete
authors.forename: Lourdes R
authors.initials: LR
authors.lastname: Desviat
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ugarte
authors.forename: Pilar
authors.initials: P
authors.lastname: Rodríguez-Pombo
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000235:genetics*; D017209:Apoptosis; D015153:Blotting, Western; D002470:Cell Survival; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007223:Infant; D007532:Isoleucine / Q000097:blood; D007930:Leucine / Q000097:blood; D008375:Maple Syrup Urine Disease / Q000175:diagnosis / Q000235:genetics*; D008856:Microscopy, Fluorescence; D009154:Mutation; D010641:Phenotype; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D000071636:Protein Phosphatase 2C; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics; D017382:Reactive Oxygen Species; D017422:Sequence Analysis, DNA; D012867:Skin / Q000166:cytology / Q000378:metabolism
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D017382:Reactive Oxygen Species; D007532:Isoleucine; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); C000607462:PPM1K protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D007930:Leucine