Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype
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.
KeywordsLactic Acidosis Null Mutation Pyruvate Dehydrogenase Pyruvate Dehydrogenase Kinase Lactic Acidemia
Polymerase chain reaction
Pyruvate dehydrogenase complex
Pyruvate dehydrogenase kinase
Pyruvate dehydrogenase phosphatase
- TCA cycle
Tricarboxylic acid cycle
We thank the Canadian Institutes for Health Research (BHR) and the Mitomarch for Kirkland for support of this research program.
- Cameron JM, Maj MC, Robinson BH (2008) Deficiency disorders of components of PDH complex: E2, E3 and E3BP deficiencies. In: Patel MS, Packer L (eds) Lipoic acid: energy production, antioxidant activity and health effects. CRC Press, West Palm Beach, pp 375–406Google Scholar
- Lissens W, De Meirleir L, Seneca S, Liebaers I, Brown GK, Brown RM, Ito M, Naito E, Kuroda Y, Kerr DS, Wexler ID, Patel MS, Robinson BH, Seyda A (2000) Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat 15:209–219PubMedCrossRefGoogle Scholar
- Maj MC, MacKay N, Levandovskiy V, Addis J, Baumgartner ER, Baumgartner MR, Robinson BH, Cameron JM (2005) Pyruvate dehydrogenase phosphatase deficiency: identification of the first mutation in two brothers and restoration of activity by protein complementation. J Clin Endocrinol Metab 90:4101–4107PubMedCrossRefGoogle Scholar
- Robinson BH (2001) Lactic acidemia (Disorders of pyruvate carboxylase, pyruvate dehydrogenase). In: Scriver CRBA, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 2275–2295Google Scholar