Human Genetics

, Volume 125, Issue 3, pp 319–326

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

  • J. M. Cameron
  • M. Maj
  • V. Levandovskiy
  • C. P. Barnett
  • S. Blaser
  • N. MacKay
  • J. Raiman
  • A. Feigenbaum
  • A. Schulze
  • B. H. Robinson
Original Investigation

DOI: 10.1007/s00439-009-0629-6

Cite this article as:
Cameron, J.M., Maj, M., Levandovskiy, V. et al. Hum Genet (2009) 125: 319. doi:10.1007/s00439-009-0629-6

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.

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

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • J. M. Cameron
    • 1
  • M. Maj
    • 1
  • V. Levandovskiy
    • 1
  • C. P. Barnett
    • 2
  • S. Blaser
    • 3
  • N. MacKay
    • 1
  • J. Raiman
    • 2
  • A. Feigenbaum
    • 2
  • A. Schulze
    • 1
    • 2
  • B. H. Robinson
    • 1
    • 4
  1. 1.Genetics and Genome Biology, The Research InstituteThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Division of Clinical and Metabolic GeneticsThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Division of NeuroradiologyThe Hospital for Sick ChildrenTorontoCanada
  4. 4.Departments of Biochemistry and PaediatricsUniversity of TorontoTorontoCanada