|Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥2,700,000 (Direct Cost: ¥2,700,000)
A deficiency of pyruvate dehydrogenase phosphatase (PDPase) has been suggested as a possible cause of congenital lactic acidemia and Leigh's disease due to a defect of activation of pyruvate dehydrogenase complex (PDHC). However, as yet, the molecular genetical analysis of PDPase in these patients has not been performed. In this study, we isolated two cDNAs for human catalytic subunits of PDPase (PDPcl and PDPc2) and detected a mutation in a patient with a defect of activation of PDHC. Human cDNA for PDPc1 and PDPc2 were highly homologous in nucleotide and protein levels to the previously reported rat PDPc1 and PDPc2, respectively. In addition, genes of PDPc1 and PDPc2 were mapped in chromosome 8, in the region q22-23, and in chromosome 3, in the region q27-28, respectively. With the nucleotide sequence determination, A716T (D239V) in cDNA for PDPc2 was detected in a patient with congenital lactic acidemia due to a defect of activation of PDHC. This amino acid was conserved in human and previously reported PDPc1 and PDPc2. These results suggest that this mutation is the primary defect of activation of PDHC in this patient.