This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Maj, M. C. Articles by Cameron, J. M. Search for Related Content PubMed PubMed Citation Articles by Maj, M. C. Articles by Cameron, J. M. Related Collections Pediatric Endocrinology Metabolism

Pyruvate Dehydrogenase Phosphatase Deficiency: Identification of the First Mutation in Two Brothers and Restoration of Activity by Protein Complementation

Metabolic Research Program, Research Institute, Hospital for Sick Children (M.C.M., N.M., V.L., J.A., B.H.R., J.M.C.), Toronto, Ontario, Canada M5G 1X8; Departments of Biochemistry and Pediatrics, University of Toronto (B.H.R.), Toronto, Ontario, Canada M5S 1A8; Universitats-Kinderspital beider Basel (E.R.B.), Postach, CH-4005 Basel, Switzerland; and Division of Metabolism and Molecular Pediatrics, University Children’s Hospital (M.R.B.), Postfach, CH-8032 Zurich, Switzerland

Address all correspondence and requests for reprints to: Dr. Brian H. Robinson, Metabolic Research Program, Research Institute, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: bhr{at}sickkids.ca.

Context: Pyruvate dehydrogenase phosphatase (PDP) deficiency has been previously reported as an enzymopathy, but the genetic basis for such a defect has never been established.

Objective: The aim of this study was to identify the cause of the defect in two patients who presented with PDP deficiency.

Patients: We studied two brothers of consanguineous parents who presented with neonatal hypotonia, elevated lactate, and less than 25% native pyruvate dehydrogenase complex (PDHc) activity in skin fibroblasts compared with controls. The activity of the complex could be restored to normal values by preincubation of the cells with dichloroacetate or by treating cell extracts with calcium.

Results: These two individuals were found to be homozygous for a 3-bp deletion in the coding sequence of the PDP isoform 1 (PDP1), which removes the amino acid residue leucine from position 213 of the protein. A recombinant version of this protein was synthesized and found to have a very reduced (<5%) ability to activate purified PDHc. Reduced steady-state levels of PDP1 in the patient’s fibroblasts coupled with the low catalytic activity of the mutant PDP1 resulted in native PDHc activity being reduced, but this could be corrected by the addition of recombinant PDP1 (wild type).

Conclusion: We have identified mutations in PDP1 in two brothers with PDP deficiency and have proven that the mutation is disease-causing. This is the first demonstration of human disease due to a mutation in PDP1.

This article has been cited by other articles:

				S. A. Cook, G. B. Collin, R. T. Bronson, J. K. Naggert, D. P. Liu, E. C. Akeson, and M. T. Davisson A Mouse Model for Meckel Syndrome Type 3 J. Am. Soc. Nephrol., April 1, 2009; 20(4): 753 - 764. [Abstract] [Full Text] [PDF]

				U. Gey, C. Czupalla, B. Hoflack, G. Rodel, and U. Krause-Buchholz Yeast Pyruvate Dehydrogenase Complex Is Regulated by a Concerted Activity of Two Kinases and Two Phosphatases J. Biol. Chem., April 11, 2008; 283(15): 9759 - 9767. [Abstract] [Full Text] [PDF]

				Z. Han, L. Zhong, A. Srivastava, and P. W. Stacpoole Pyruvate Dehydrogenase Complex Deficiency Caused by Ubiquitination and Proteasome-mediated Degradation of the E1 Subunit J. Biol. Chem., January 4, 2008; 283(1): 237 - 243. [Abstract] [Full Text] [PDF]