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Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype

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Abstract

Pyruvate dehydrogenase phosphatase deficiency has previously only been confirmed at the molecular level in two brothers and two breeds of dog with exercise intolerance. A female patient, who died at 6 months, presented with lactic acidemia in the neonatal period with serum lactate levels ranging from 2.5 to 17 mM. Failure of dichloroacetate to activate the PDH complex in skin fibroblasts was evident, but not in early passages. A homozygous c.277G > T (p.E93X) nonsense mutation in the PDP1 gene was identified in genomic DNA and immunoblotting showed a complete absence of PDP1 protein in mitochondria. Native PDHC activity could be restored by the addition of either recombinant PDP1 or PDP2. This highlights the role of PDP2, the second phosphatase isoform, in PDP1-deficient patients for the first time. We conclude that the severity of the clinical course associated with PDP1 deficiency can be quite variable depending on the exact nature of the molecular defect.

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Abbreviations

Bp:

Base pair

coA:

Coenzyme A

DCA:

Dichloroacetate

PCR:

Polymerase chain reaction

PDH:

Pyruvate dehydrogenase

PDHC:

Pyruvate dehydrogenase complex

PDK:

Pyruvate dehydrogenase kinase

PDP:

Pyruvate dehydrogenase phosphatase

RT:

Reverse transcriptase

TCA:

Trichloroacetic acid

TCA cycle:

Tricarboxylic acid cycle

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Acknowledgments

We thank the Canadian Institutes for Health Research (BHR) and the Mitomarch for Kirkland for support of this research program.

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Authors and Affiliations

  1. Genetics and Genome Biology, The Research Institute, The Hospital for Sick Children, Toronto, M5G 1X8, Canada

    J. M. Cameron, M. Maj, V. Levandovskiy, N. MacKay, A. Schulze & B. H. Robinson

  2. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, M5G 1X8, Canada

    C. P. Barnett, J. Raiman, A. Feigenbaum & A. Schulze

  3. Division of Neuroradiology, The Hospital for Sick Children, Toronto, M5G 1X8, Canada

    S. Blaser

  4. Departments of Biochemistry and Paediatrics, University of Toronto, 1 King’s College Circle, Toronto, ON, M5S 1A8, Canada

    B. H. Robinson

Authors
  1. J. M. Cameron
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  2. M. Maj
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  3. V. Levandovskiy
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  4. C. P. Barnett
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  5. S. Blaser
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  6. N. MacKay
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  7. J. Raiman
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  8. A. Feigenbaum
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  9. A. Schulze
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  10. B. H. Robinson
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Corresponding author

Correspondence to B. H. Robinson.

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Cameron, J.M., Maj, M., Levandovskiy, V. et al. Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype. Hum Genet 125, 319–326 (2009). https://doi.org/10.1007/s00439-009-0629-6

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  • DOI: https://doi.org/10.1007/s00439-009-0629-6

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