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A Novel Regulatory Defect in the Branched‐Chain α‐Keto Acid Dehydrogenase Complex Due to a Mutation in the PPM 1 K Gene Causes a Mild Variant Phenotype of Maple Syrup Urine Disease
Author(s) -
Oyarzabal Alfonso,
MartínezPardo Mercedes,
Merinero Begoña,
Navarrete Rosa,
Desviat Lourdes R,
Ugarte Magdalena,
RodríguezPombo Pilar
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22242
Subject(s) - biology , mutation , genetics , maple syrup urine disease , microbiology and biotechnology , pyruvate dehydrogenase complex , phenotype , gene , biochemistry , amino acid , enzyme , leucine
This article describes a hitherto unreported involvement of the phosphatase PP 2 C m, 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, PPM 1 K , revealed a homozygous c.417_418delTA change predicted to result in a truncated, unstable protein. No PP 2 C m mutant protein was detected in immunocytochemical or W estern blot expression analyses. The transient expression of wild‐type PPM 1 K in PP 2 C m‐deficient fibroblasts recovered 35% of normal BCKDH activity. As PP 2 C m has been described essential for cell survival, apoptosis and metabolism, the impact of its deficiency on specific metabolic stress variables was evaluated in PP 2 C m‐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.