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

• DOI: 10.1210/jc.2005-0123
• Publication Date: 2005-07-07T06:50:02Z
• Authors: Mary C. Maj; Neviana MacKay; Valeriy Levandovskiy; Jane Addis; E. Regula Baumgar...; Matthias R. Baumg...; Brian H. Robinson; Jessie M. Cameron
• Keywords: Identification; Protein-fragment complementation assay

Abstract Context: Pyruvate dehydrogenase phosphatase (PDP) deficiency has been previously reported as an enzymopathy, but the genetic basis for such a defect never established. Objective: The aim of this study was to identify cause in two patients who presented with PDP deficiency. Patients: We studied brothers consanguineous parents neonatal hypotonia, elevated lactate, and less than 25% native pyruvate complex (PDHc) activity skin fibroblasts compared controls. could be restored normal values by preincubation cells dichloroacetate or treating cell extracts calcium. Results: These individuals were found homozygous 3-bp deletion coding sequence isoform 1 (PDP1), which removes amino acid residue leucine from position 213 protein. A recombinant version protein synthesized have very reduced (<5%) ability activate purified PDHc. Reduced steady-state levels PDP1 patient’s coupled low catalytic mutant resulted PDHc being reduced, corrected addition (wild type). Conclusion: identified mutations proven that mutation is disease-causing. This first demonstration human disease due PDP1.