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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

Authors

  • Alfonso Oyarzabal,

    1. Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, IDIPAZ, Madrid, Spain
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  • Mercedes Martínez-Pardo,

    1. Servicio de Pediatría, Hospital Universitario Ramón y Cajal, Madrid, Spain
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  • Begoña Merinero,

    1. Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, IDIPAZ, Madrid, Spain
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  • Rosa Navarrete,

    1. Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, IDIPAZ, Madrid, Spain
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  • Lourdes R Desviat,

    1. Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, IDIPAZ, Madrid, Spain
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  • Magdalena Ugarte,

    1. Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, IDIPAZ, Madrid, Spain
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  • Pilar Rodríguez-Pombo

    Corresponding author
    • Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular “Severo Ochoa” CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, IDIPAZ, Madrid, Spain
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  • Communicated by Jan Kraus

  • Contract grant sponsors: Fundación Ramón Areces (XVI Concurso Nacional Investigación Científica y Técnica); Spanish Ministerio de Sanidad y Consumo, (PI080131) and Ciencia y Tecnología (SAF2010–17272).

Correspondence to: Pilar Rodríguez-Pombo, Centro de Biología Molecular “Severo Ochoa”, Laboratorio 204, C/ Nicolás Cabrera No. 1, Universidad Autónoma de Madrid, 28049 Madrid, Spain. E-mail: mprodriguez@cbm.uam.es

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.

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