Molecular Genetical Analysis of New Cause for Congenital Lactic Acidemia

丙酮酸脱氢酶磷酸酶(PDPase)缺陷可能是先天性乳酸血症和Leigh病的原因之一，这是由于丙酮酸脱氢酶复合体(PDHC)激活缺陷所致。然而，到目前为止，对这些患者的PDPase的分子遗传学分析还没有进行。在这项研究中，我们分离了两个人类PDPase催化亚基的cDNA(PDPc1和PDPc2)，并在一名PDHC激活缺陷的患者中检测到了突变。人PDPc1和PDPc2基因在核苷酸和蛋白质水平上分别与已报道的大鼠PDPc1和PDPc2高度同源。此外，PDPc1和PDPc2基因分别定位在8号染色体Q22-23区和3号染色体Q27-28区。通过核苷酸序列测定，在1例先天性乳酸血症患者中检测到PDPc2基因的A716T(D239V)，这是由于PDHC激活缺陷所致。该氨基酸在人和先前报道的PDPc1和PDPc2中是保守的。这些结果表明，该突变是该患者PDHC激活的主要缺陷。

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.