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Título: | 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 |
Autor: | Oyarzábal, Alfonso CSIC ORCID; Martínez Pardo, Mercedes; Merinero, Begoña CSIC; Navarrete, Rosa; Desviat, Lourdes R. CSIC ORCID | Palabras clave: | PPM1K Maple syrup Urine disease PP2Cm phosphatase MAP kinase |
Fecha de publicación: | 2013 | Editor: | John Wiley & Sons | Citación: | Human Mutation 34: 355- 362 (2013) | Resumen: | 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. | URI: | http://hdl.handle.net/10261/117068 | DOI: | 10.1002/humu.22242 | Identificadores: | doi: 10.1002/humu.22242 issn: 1059-7794 |
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