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

Hum Mutat. 2013 Feb;34(2):355-62. doi: 10.1002/humu.22242. Epub 2012 Dec 12.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / genetics*
  • Apoptosis
  • Blotting, Western
  • Cell Survival
  • DNA Mutational Analysis
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Frequency
  • Genotype
  • Humans
  • Infant
  • Isoleucine / blood
  • Leucine / blood
  • Maple Syrup Urine Disease / diagnosis
  • Maple Syrup Urine Disease / genetics*
  • Microscopy, Fluorescence
  • Mutation
  • Phenotype
  • Phosphoprotein Phosphatases / genetics*
  • Protein Phosphatase 2C
  • Pyruvate Dehydrogenase Complex / genetics
  • Reactive Oxygen Species
  • Sequence Analysis, DNA
  • Skin / cytology
  • Skin / metabolism


  • Pyruvate Dehydrogenase Complex
  • Reactive Oxygen Species
  • Isoleucine
  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
  • PPM1K protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C
  • Leucine