Molecular Genetical Analysis of New Cause for Congenital Lactic Acidemia

丙酮酸脱氢酶磷酸酶（PDHC）的缺陷被认为是先天性乳酸血症和Leigh病的可能原因，因为丙酮酸脱氢酶复合物（PDHC）的激活缺陷。然而，到目前为止，还没有对这些患者进行PDE 2的分子遗传学分析。在这项研究中，我们分离了两个人PDHC催化亚基（PDPc 1和PDPc 2）的cDNA，并在一个PDHC活化缺陷的患者中检测到突变。人PDPc 1和PDPc 2的cDNA在核苷酸和蛋白质水平上分别与先前报道的大鼠PDPc 1和PDPc 2高度同源。此外，PDPc 1和PDPc 2的基因分别定位在8号染色体的q22-23区域和3号染色体的q27-28区域。通过核苷酸序列测定，在由于PDHC活化缺陷而患有先天性乳酸血症的患者中检测到PDPc 2 cDNA中的A716 T（D239 V）。该氨基酸在人类和先前报道的PDPc 1和PDPc 2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.