A Novel Regulatory Defect in the Branched-Chain -Keto Acid Dehydrogenase Complex Due to a Mutation in the PPM1K Gene Causes a Mild Variant Phenotype of Maple Syrup Urine Disease

作者：Oyarzabal Alfonso; Martinez Pardo Mercedes; Merinero Begona; Navarrete Rosa; Desviat Lourdes R; Ugarte Magdalena; Rodriguez Pombo Pilar^*

来源：Human Mutation, 2013, 34(2): 355-362.

DOI：10.1002/humu.22242

• PP2Cm phosphatase
• PPM1K
• maple syrup urine disease
• MAP kinase

This article describes a hitherto unreported involvement of the phosphatase PP2Cm, a recently described member of the branched-chain -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%26apos;s MSUD phenotypeand perhaps others.

• 出版日期2013-2